TMLI Plus Chemotherapy in High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia (TMLI-MA)

Phase II Study of TMLI Administered in Combination With a Myeloablative Regimen (Cyclophosphamide + Etoposide) for Allogeneic Hematopoietic Stem Cell Transplantation in Patients With High-risk Myelodysplastic Syndrome or Acute Myeloid Leukemia

Single-arm, single-center phase II trial to evaluate the antileukemic activity and safety/tolerability of TMLI/cyclophosphamide and etoposide conditioning regimen followed by allogeneic hematopoietic stem cell transplantation in patients with high-risk myelodysplastic syndrome or acute myeloid leukemia.

Study Overview

• Status: Not yet recruiting
• Conditions: Myelodysplastic Syndromes; Myeloid Leukemia, Acute
• Intervention / Treatment: Drug: Total bone marrow and lymphoid irradiation/cyclophosphamide/etoposide

Detailed Description

The aim of this study is the evaluation of the antitumor activity of the conditioning regimen with TMLI, cyclophosphamide and etoposide followed by allogeneic hematopoietic stem cell transplantation by means of the progression-free survival at 2 years after a safety-lead phase.

The determination of the complete remission rate at day 30 post-transplant, the estimation of overall survival, the cumulative incidence of recurrence/progression, and non-relapse mortality at 100 days, 1 year, and 2 years, the Minima Residual Disease monitoring at 30, 90, 180, 270 days and 1 year, 1 year and a half and 2 years post-transplant, and the assessment early and late toxicities/complications by organ and severity, as well as dose/dose-volume toxicity characterization across organs, including acute/chronic graft-versus-host disease, infection, and long-term complications are included as secondary objectives.

• Study Type: Interventional
• Enrollment (Estimated): 58
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Clara M Rosso Fernández, MD-PhD; Phone Number: +34955013414; Email: claram.rosso.sspa@juntadeandalucia.es
• Study Contact Backup: Name: José Antonio Pérez Simón, MD-PhD; Phone Number: +34955013260; Email: josea.perez.simon.sspa@juntadeandalucia.es

Study Locations

• Spain
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
    • Contact: Jose-Antonio Perez-Simon; Phone Number: 0034 0034955013260; Email: josea.perez.simon.sspa@juntadeandalucia.es

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• The participant has the ability and willingness to sign the informed consent document
• Age ≥18 to ≤50 years.
• Karnofsky's performance status should be ≥70%.
• Patients with myelodysplastic syndrome/acute myeloid leukemia or acute myeloid leukemia with relapsed/refractory active disease, or in complete remission or morphologic leukemia-free state with evidence of measurable residual disease as assessed by multiparameter flow cytometry (≥ 0,1%) or next-generation sequencing
• All candidates for this study must have an Human leukocyte antigens (A, B, C, DR) identical siblings who are willing to donate bone marrow or peripheral blood hematopoietic progenitors or an 8/8 matched unrelated donor. A single allele mismatch in A, B, C or DR beta chain 1 shall be allowed
• Total bilirubin ≤ 1.5 x upper limit of normal or 3 x upper limit of normal for Gilbert's disease.
• serum glutamate oxaloacetate transaminase & serum glutamate pyruvate transaminaseT ≤ 5 x upper limit of normal.
• Serum creatinine ≤ 1.3 mg/dL or creatinine clearance measured ≥ 80 mL/min for 24 hours of urine collection
• Women of childbearing age only: Negative urine or serum pregnancy test
• Pulmonary function tests: forced expiratory volume in one second and Carbon Monoxide Diffusion Capacity (adjusted for Hb) ≥ 50% from expected normal value
• Patients should undergo cardiac evaluation with an electrocardiogram showing no ischemic changes or clinically relevant arrhythmia, and a ≥50% ejection fraction established by Multi-Gated Acquisition Scan or echocardiogram
• Men and women of childbearing potential agree to use appropriate contraceptives (hormonal or barrier contraception or abstinence) prior to study entry and for six months following the duration of study participation
• The time elapsed since the end of the last induction or reinduction cycle must be greater than or equal to 14 days

Exclusion Criteria:

• Patients who have received a previous autologous (within the last year) or allogeneic transplant (at any time) are excluded
• Previous radiation therapy, which would preclude the use of total bone marrow and lymphoid irradiation
• Plans during the trial to receive any other investigational (non-trial-related) agents
• Uncontrolled disease, including ongoing or active infection
• History of allergic reactions attributed to compounds of chemical or biological composition similar to cyclophosphamide or etoposide
• Patients with other active malignancies are not eligible for this study, other than the malignancies discussed
• Patients with a psychological or medical condition that the patient's physician deems unacceptable to proceed with allogeneic hematopoietic stem cell transplantation
• Women who plan to become pregnant or breastfeed during the trial
• Patients who do not agree to practice effective forms of contraception
• Subjects who, in the opinion of the investigator, may not be able to meet the safety control requirements of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Single arm; This trial is designed to evaluate the antileukemic activity of an Total bone marrow and lymphoid irradiation/cyclophosphamide/etoposide conditioning regimen for allogeneic hematopoietic stem cell transplantation, in patients with high-risk myelodysplastic syndromes and acute myeloid leukemia, as assessed by 2-year progression-free survival. The first 6-18 patients enrolled/treated in this study will be part of a safety sub-analysis, so patients will be assigned to the dose level that is currently open once they are verified to be eligible; up to three dose levels can be studied.

Drug: Total bone marrow and lymphoid irradiation/cyclophosphamide/etoposide; Evaluate the antileukemic activity of an total bone marrow and lymphoid irradiation/cyclophosphamide/etoposide conditioning regimen for allogeneic hematopoietic stem cell transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Time from the start of treatment to the date of death, disease relapse/progression, or date of last follow-up.	From the start of therapy to 2 years after post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Quantification of time of patients who are still alive	From the start of therapy to 2 years after post-transplant
Cumulative incidence of recurrence/progression	The event is relapse/progression either extramedullary or at bone marrow	From the start of therapy to 2 years after post-transplant
Complete remission rate	The event is whether or not the patient has a documented complete remission	From the day of infusion to the day 30 post-transplant
Non-relapse mortality	Number of deaths from causes other than relapse or progression	From the start of therapy until 2 years after post-transplant
Measurable residual disease	Measurable residual disease monitoring assessed by multiparameter flow cytometry	At 30, 90, 180 days and 1 year, 1.5 year and 2 years post-transplant
Incidence of infection	Describe the infections.	2 years after post-transplant
Adverse Events	Describe the adverse event	2 years after post-transplant
Acute graft-versus-host disease grades 2-4 and 3-4	This point is classified according to the consensus MAGIC classification	100 days post-transplant
Chronic graft-versus-host disease	Describe the chronic graft-versus-host disease according to the National Institutes of Health Stroke Scale consensus staging.	2 years after post-transplant

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Investigators: Principal Investigator: José Antonio Pérez Simón, MD-PhD, Fundación para la Gestión de la Investigación en Salud de Sevilla

Study record dates

Study Major Dates

• Study Start (Estimated): December 30, 2024
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2028

Study Registration Dates

• First Submitted: August 28, 2024
• First Submitted That Met QC Criteria: September 16, 2024
• First Posted (Estimated): September 19, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 16, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Acute myeloid leukemia; High-Risk myelodysplastic syndrome; Total narrow and lymphoid irradiation
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cyclophosphamide; Etoposide
• Other Study ID Numbers: TMLI-MA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No