Neoplasms

Blood and Lymph Conditions

All Conditions

Leukemia

Leukemia, Myeloid

Neoplasms by Histologic Type

Hematologic Diseases

Antineoplastic Agents

All Drugs and Chemicals

Fludarabine

Fludarabine phosphate

Busulfan

Thiotepa

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Alkylating Agents

Antineoplastic Agents, Alkylating

Reduced toxicity conditioning regimen (thiotepa, busulfan, fludarabine and ATG) followed by unrelated cord blood allogeneic stem cell transplant for high risk myeloïd malignancies.

The conditioning regimen will include:

* IV Thiotepa (5 mg/Kg/day for 2 days) (Day -7 and -6)
* IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2)
* IV Busulfan (Busilvex 130 mg/m2/day for 3 days) (Day-5, -4 and -3)
* IV Anti-thymocyte globuline (Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)

In patient with co-morbidities and/or older than 60 years, conditioning could be reduced after consulting the coordinator of the study:

* IV Thiotepa (5 mg/Kg/day for 2 days) (Day -6)
* IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2)
* IV Busulfan (Busilvex 100 mg/m2/day for 3 days) (Day-5, -4 and -3)
* IV Anti-thymocyte globuline (Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)

IV Thiotepa (5 mg/Kg/day for 2 days) (Day -7 and -6) or IV Thiotepa (5 mg/Kg/day for 2 days) (Day -6)

IV Thiotepa

IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2)

IV Fludarabine

(Busilvex 130 mg/m2/day for 3 days) (Day-5, -4 and -3) or (Busilvex 100 mg/m2/day for 3 days) (Day-5, -4 and -3)

IV Busulfan

(Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)

IV Anti-thymocyte globuline

Marie Thérèse RUBIO

Allogeneic cord blood stem cell transplantation is a potentially curative therapy for patients with haematological malignancies. We have extensive experience with the use of Cord Blood Transplantation (CBT) in patients with advanced myeloid malignancies. In adults however, the 40% Non-Relapse Mortality (NRM) rate observed after CBT conditioned with a myeloablative conditioning has encouraged the development of CBT with Reduced Intensity Conditioning (RIC). Our previous national CBT protocol (the Minicord French protocol - NCT00797758) showed that RIC CBT can reduce NRM, but relapse remains the main post-transplant event (\>30% at one year). Thus, the development of reduced toxicity rather than RIC conditioning for CBT is warranted in order to improve the outcome of such transplants by limiting NRM and reducing relapse rate. The Fludarabine, ATG and intensified doses of IV Busulfan (9.6 mg/Kg total dose) regimen is a well-established preparative regimen for reduced-intensity/toxicity conditioning prior to allogeneic stem cell transplantation using peripheral blood stem cells mobilized with G-CSF (ClinicalTrials.gov Identifier: NCT00841724). However, such regimen is likely not sufficient to allow for CB cell engraftment. Thiotepa is an alkylating and radio-mimetic agent with a large anti-tumor activity including leukemic cells, the ability to cross the blood-brain barrier and to improve engraftment of hematopoietic stem cells. This drug has been combined to usual conditioning regimen without increasing the toxicity but improving the engraftment rate and potentially reducing the relapse rate. Thus, in the context of adult CBT for high risk myeloid malignancies, we propose to prospectively evaluate a reduced toxicity conditioning based on the association of Thiotepa, Fludarabine, IV Busulfan and ATG with the objective to achieve acceptable NRM rates, and to allow for improved anti-leukemic control based on the cytotoxic component of the conditioning regimen itself, while waiting for the long term immune-mediated disease control (GVL effect).

Reduced Toxicity Conditioning Prior to Unrelated Cord Cell Transplantation for High Risk Myeloid Malignancies

Cumulative incidence of NRM at 12 months after transplantation : Safety and efficacy of the pre-transplant reduced toxicity conditioning regimen

Incidence of neutrophil engraftment (day and proportion of patients reaching neutrophils \>0.5x109/L); and platelets recovery (day and proportion of patients reaching platelets \> 20 x 109 / L without transfusion) after transplantation

Incidence and severity of acute GVHD (diagnosed and graded as standard criteria)

Incidence and severity of chronic GVHD (diagnosed and graded as standard criteria detailed )

Incidence of disease relapse at one year after transplantation (relapse is defined on the basis of morphologica evidence of leukemic cells in the bone marrow or other sites)

Evaluation of the quality of life (using a french translation of the FACT-BMT (version 4.0)

Assistance Publique - Hôpitaux de Paris

Antirheumatic Agents

Anti-Infective Agents

Cyclophosphamide

Tacrolimus

Clofarabine

Vidarabine

Antiviral Agents

Calcineurin Inhibitors

Enzyme Inhibitors

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).

Single UM171-Expanded CB transplant (CD34+: 2.5-50x10\^5/kg, CD3+\>1x10\^6/kg)

ECT-001-CB (UM171-Expanded Cord Blood Transplant)

Jaap Jan Boelens, MD, PhD

Andromachi Scaradavou, MD

Jaap J Boelens, MD

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).

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

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

Incidence and severity of AEs according to the modified (for HSCT) CTCAE (v. 5.0)

Incidence of relapse will be measured from time of transplant

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

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

Incidence of acute and chronic GVHD will be measured by NIH criteria

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

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)

Incidence of pre-engraftment/engraftment syndrome requiring therapy

Duration of transplant admission and number of days in hospital in 1st 100 days, and last day of fever (\>38°C) prior to engraftment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Reduced Toxicity Conditioning Prior to Unrelated Cord Cell Transplantation for High Risk Myeloid Malignancies	NCT02333838	Leukemia, Myelo...	IV Thiotepa IV Fludarabine IV Busulfan IV Anti-thymocy...	18 Years - 65 Years	Assistance Publique - Hôpitaux de Paris
US Study of ECT-001-CB in Pediatric and Young Adult Patients With High-Risk Myeloid Malignancies	NCT04990323	High Risk Myelo... Cord Blood Tran...	ECT-001-CB (UM1...	0 Years - 21 Years	ExCellThera inc.
Reduced Toxicity Conditioning Prior to Unrelated Cord Cell Transplantation for High Risk Myeloid Malignancies	NCT02333838	Leukemia, Myelo...	IV Thiotepa IV Fludarabine IV Busulfan IV Anti-thymocy...	18 Years - 65 Years	Assistance Publique - Hôpitaux de Paris

Spots Global Cancer Trial Database for high risk myeloid malignancies