Expanded Cord Blood Transplant for High-Risk Leukemia

Overseen By Andromachi Scaradavou, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ExCellThera inc.

Disqualifiers: Uncontrolled infection, HIV, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

Trial Summary

What is the purpose of this trial?

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).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment ECT-001-CB (UM171-Expanded Cord Blood Transplant) for high-risk leukemia?

Research shows that UM171-expanded cord blood transplants have lower nonrelapse mortality and higher progression-free survival compared to traditional cord blood and matched-unrelated donor transplants. Additionally, patients receiving UM171-expanded cord blood experienced less severe acute and chronic graft-versus-host disease. ^{1 2 3 4 5}

Is the UM171-expanded cord blood transplant safe for humans?

A phase 1-2 trial of UM171-expanded cord blood transplants showed that it is safe and has favorable outcomes compared to other types of transplants. Patients experienced lower nonrelapse mortality and fewer severe cases of graft-versus-host disease, which is a condition where the transplanted cells attack the recipient's body. ^{1 2 6 7 8}

How is the ECT-001-CB treatment different from other treatments for high-risk leukemia?

The ECT-001-CB treatment is unique because it uses UM171 to expand cord blood stem cells, which can enhance blood cell recovery and reduce complications like graft-versus-host disease (a condition where the transplanted cells attack the recipient's body). This approach aims to improve outcomes for patients who do not have a suitable donor, offering a novel option compared to traditional cord blood transplants. ^{1 3 9 10 11}

Eligibility Criteria

This trial is for pediatric and young adult patients with high-risk myeloid malignancies, such as Acute Myeloid Leukemia or Chronic Myelogenous Leukemia in blast crisis. Participants need a suitable cord blood match, good organ function, and no uncontrolled infections or other recent treatments that could affect the study.

Inclusion Criteria

Acute Myeloid Leukemia with chemo-refractory relapse (MRD+), primary induction failure, relapse after previous allogeneic or autologous transplant (>4 months), secondary or therapy-related MDS/AML, poor response to induction, Myelodysplastic syndrome with 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 with MRD+ or relapse after previous transplant (>4 months), JMML with availability of 2 ≥ 4/8 HLA matched CBU, Lansky / Karnofsky >60%, specific blood count requirements, specific liver function tests, specific kidney function tests, specific cardiac function test, signed written informed consent, and female patients of childbearing potential must have a negative serum pregnancy test within 7 days of enrollment and must 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 with expected survival 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, pregnancy, breastfeeding, unwillingness to use appropriate contraception, participation in a trial with an investigational agent within 30 days prior to entry in the study, and any abnormal condition or lab result that is considered capable of altering patient's condition or study outcome.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Patients receive a myeloablative conditioning regimen (Preferred: Clo/Flu/Bu90, Alternative: MIDI) before transplantation

1 week

Transplantation

The CD34+ product is expanded with UM171 and infused on Day 0, while the CD34- product is infused on Day +1 post-transplant

1 week

Engraftment and Early Recovery

Monitoring for hematologic engraftment and early recovery, including neutrophil and platelet engraftment

100 days

Follow-up

Participants are monitored for safety, effectiveness, and incidence of GVHD and infections post-transplant

2 years

Treatment Details

Interventions

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

Trial Overview The trial tests ECT-001-CB (UM171-Expanded Cord Blood Transplant) to improve outcomes of cord blood transplants by increasing cell dose and reducing complications like graft-versus-host disease. The first stage includes 12 patients; if successful, it will expand to more centers with additional participants.

Participant Groups

Group I: ECT-001-Expanded CB Experimental Treatment 1 Intervention

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).

ECT-001-CB (UM171-Expanded Cord Blood Transplant) is already approved in European Union, United States for the following indications:

Approved in European Union as ECT-001-CB for:

• Haematological malignancies

Approved in United States as ECT-001-CB for:

• High-risk myeloid malignancies

Who Is Running the Clinical Trial?

ExCellThera inc.

Lead Sponsor

Trials

5

Recruited

90+

Memorial Sloan Kettering Cancer Center

Collaborator

Trials

1,998

Recruited

602,000+

Findings from Research

Double-unit cord blood transplantation (CBT) has significantly improved engraftment and reduced transplant-related mortality in adult patients with hematologic malignancies, addressing the limitations of single-unit CBT due to cell dose.

Despite only one unit typically sustaining donor hematopoiesis, double-unit CBT offers insights into transplant biology and may protect against relapse, making it a promising option for a wider range of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cord blood transplants: one, two or more units? Avery, S., Barker, JN.[2010]

In a study involving 137 patients, UM171-expanded cord blood transplants showed lower nonrelapse mortality (NRM) and improved progression-free survival (PFS) and graft-versus-host disease-free relapse-free survival (GRFS) compared to unmanipulated cord blood transplants.

When compared to matched-unrelated donor (MUD) transplants, UM171 recipients had significantly lower NRM and experienced less severe acute and chronic graft-versus-host disease, indicating a safer and more effective option for patients undergoing transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved outcomes of UM171-expanded cord blood transplantation compared with other graft sources: real-world evidence. Cohen, S., Bambace, N., Ahmad, I., et al.[2023]

The study demonstrated that UM171 can successfully expand cord blood stem cells, allowing for the use of smaller single cord blood units without compromising engraftment in patients with hematological malignancies, with a 96% success rate in expansion.

The safety profile was acceptable, with no unexpected adverse events, although there were common complications like febrile neutropenia and one treatment-related death, indicating that while promising, further investigation in randomized trials is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1-2 safety and feasibility study. Cohen, S., Roy, J., Lachance, S., et al.[2020]

In a study of 90 adults undergoing double-unit cord blood transplantation (CBT) with an intermediate intensity conditioning regimen, the procedure achieved a high sustained engraftment rate of 99% and a 3-year overall survival rate of 82%.

The use of unmanipulated grafts with significant HLA mismatches allowed for broader application of CBT, demonstrating low relapse rates and effective graft-versus-leukemia effects, even in patients with minimal residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults. Barker, JN., Devlin, SM., Naputo, KA., et al.[2023]

Ex vivo expansion of a single cord blood unit (CBU) using mesenchymal stromal cells (MSCs) significantly enhances the hematopoiesis of an unexpanded CBU in a double cord blood transplantation (DCBT) setting, leading to improved survival rates in mice.

The expanded CBU resulted in a lower incidence of graft versus host disease (GVHD), likely due to an increase in regulatory T cells, suggesting a safer approach to DCBT with potential benefits for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mesenchymal stromal cell supported umbilical cord blood ex vivo expansion enhances regulatory T cells and reduces graft versus host disease. Fan, X., Gay, FP., Ong, SY., et al.[2018]

Cord blood transplantation (CBT) is increasingly popular in Japan, with over 1,200 procedures performed annually, and it accounts for nearly one-third of all CBTs worldwide, benefiting from factors like smaller body size and lower costs.

Recent findings indicate that while CBT has unique challenges, such as specific infectious complications and mechanisms of engraftment failure, it shows comparable survival rates to HLA-matched bone marrow or peripheral blood transplants, suggesting its efficacy as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cord blood transplantation in Japan. Uchida, N.[2017]

Cord blood transplantation (CBT) is recognized as a valuable alternative source for stem cell transplants, and future efforts should focus on enhancing its applications and methods, including personalized protocols and advanced therapies to improve patient outcomes.

The concept of 'CB banking 2.0' is proposed, which aims to expand the role of cord blood banks beyond transplantation to support cell therapy and regenerative medicine, necessitating international collaboration among specialists and clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The wider perspective: cord blood banks and their future prospects. Querol, S., Rubinstein, P., Madrigal, A.[2021]

In a phase 2 study involving 62 adult patients with leukemia and myelodysplastic syndrome, single-unit cord blood transplantation (CBT) demonstrated an 85% survival rate at day 180, indicating its efficacy as a treatment option.

The study also reported a high neutrophil engraftment rate of 92%, with manageable incidences of graft-versus-host disease, suggesting that CBT can be a safe alternative when a well-HLA-matched unrelated donor is not available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Phase 2 Study of Umbilical Cord Blood Transplantation in Adult Acute Leukemia and Myelodysplastic Syndrome. Terakura, S., Nishida, T., Sawa, M., et al.[2021]

A new device allows for the selective thawing of just 1 mL of umbilical cord blood (UCB), enabling the remaining UCB to be preserved for future use, which could enhance treatment options for leukemia.

This method successfully expanded large numbers of natural killer (NK) cells from the thawed UCB, which showed strong cytotoxicity against leukemia cells, suggesting potential for preventing relapse and reducing complications like graft-versus-host disease after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. Vasu, S., Berg, M., Davidson-Moncada, J., et al.[2021]

In a study involving 101 patients, umbilical cord blood (UCB) transplantation using expanded CD34+ stem cells significantly improved 100-day survival rates (84.2%) compared to double-unit cord blood transplantation (DUCBT) (74.6%).

The carlecortemcel-L group also experienced faster engraftment of neutrophils and platelets, indicating enhanced recovery post-transplant, while rates of graft-versus-host disease were similar between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cohort-Controlled Comparison of Umbilical Cord Blood Transplantation Using Carlecortemcel-L, a Single Progenitor-Enriched Cord Blood, to Double Cord Blood Unit Transplantation. Stiff, PJ., Montesinos, P., Peled, T., et al.[2019]

Umbilical cord blood (UCB) has become a viable alternative for stem cell transplantation, especially for patients without HLA-matched donors, with over 3500 transplants performed, primarily in children but also in adults.

UCB's unique properties allow for the use of HLA-mismatched grafts without significantly increasing the risk of severe graft versus host disease, and its rich NK cell content can enhance the graft versus leukemia effect, although challenges like low stem cell yields remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Umbilical cord blood transplantation--how, when and for whom? Cohen, Y., Nagler, A.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Cord blood transplants: one, two or more units? [2010]

2. United States pubmed.ncbi.nlm.nih.gov

Improved outcomes of UM171-expanded cord blood transplantation compared with other graft sources: real-world evidence. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1-2 safety and feasibility study. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Mesenchymal stromal cell supported umbilical cord blood ex vivo expansion enhances regulatory T cells and reduces graft versus host disease. [2018]

6. Japan pubmed.ncbi.nlm.nih.gov

Cord blood transplantation in Japan. [2017]

7. England pubmed.ncbi.nlm.nih.gov

The wider perspective: cord blood banks and their future prospects. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Prospective Phase 2 Study of Umbilical Cord Blood Transplantation in Adult Acute Leukemia and Myelodysplastic Syndrome. [2021]

9. England pubmed.ncbi.nlm.nih.gov

A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Cohort-Controlled Comparison of Umbilical Cord Blood Transplantation Using Carlecortemcel-L, a Single Progenitor-Enriched Cord Blood, to Double Cord Blood Unit Transplantation. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Umbilical cord blood transplantation--how, when and for whom? [2022]