225Ac-DOTA-Anti-CD38 Daratumumab Monoclonal Antibody With Fludarabine, Melphalan and Total Marrow and Lymphoid Irradiation as Conditioning Treatment for Donor Stem Cell Transplant in Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia and Myelodysplastic Syndrome

Acute Myeloid Leukemia Clinical Trial

Official title: Phase I Study of Escalating Doses of 225Ac-DOTA-Anti-CD38 Daratumumab Monoclonal Antibody Added to the Conditioning Regimen of Fludarabine, Melphalan and Organ Sparing Total Marrow and Lymphoid Irradiation (TMLI) as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia and Myelodysplastic Syndrome

Status Not yet recruiting

Clinical Trial Summary

This phase I trial tests the safety, side effects, best dose, and effectiveness of 225Ac-DOTA-Anti-CD38 daratumumab monoclonal antibody in combination with fludarabine, melphalan and total marrow and lymphoid irradiation (TMLI) as conditioning treatment for donor stem cell transplant in patients with high-risk acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Radioimmunotherapy is treatment with a radioactive substance that is linked to a monoclonal antibody, such as daratumumab, that will find and attach to cancer cells. Radiation given off by the radioisotope my help kill the cancer cells. Chemotherapy drugs, such as fludarabine and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. TMLI is a targeted form of body radiation that targets marrow, lymph node chains, and the spleen. It is designed to reduce radiation-associated side effects and maximize therapy effect. Actinium Ac 225-DOTA-daratumumab combined with fludarabine, melphalan and TMLI may be safe, tolerable, and/or effective as conditioning treatment for donor stem cell transplant in patients with high-risk AML, ALL, and MDS.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. Describe toxicities attributable to actinium Ac 225-DOTA-daratumumab (225Ac-DOTA-anti-CD38 daratumumab) radioimmunotherapy by dose level in patients treated under this regimen.

II. Determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of 225Ac-DOTA-anti-CD38 daratumumab radioimmunotherapy with fixed doses of organ sparing TMLI (12 Gy), fludarabine and melphalan (FM100) as conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) for treatment of high-risk acute myeloid leukemias, acute lymphoblastic leukemia or myelodysplastic syndrome (MDS), in patients who are not eligible for standard myeloablative regimens.

SECONDARY OBJECTIVES:

I. Evaluate the safety of the regimen, at each dose level, by assessing the following:

Ia. Type, frequency, severity, attribution, time course and duration of adverse events, including acute/chronic graft-versus-host disease (GVHD), infection and delayed engraftment.

II. Estimate overall survival (OS), event-free survival (EFS), GVHD relapse free survival (GRFS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

III. Describe biodistribution, pharmacokinetics and organ dosimetry of 225Ac-DOTA-daratumumab.

OUTLINE: This is a dose escalation of actinium Ac 225-DOTA-Daratumumab in combination with fludarabine, melphalan and TMLI.

Patients receive daratumumab intravenously (IV) over 45 minutes followed by indium In 111-DOTA-daratumumab IV over 15 minutes and actinium Ac 225-DOTA-daratumumab IV over ~20-40 minutes on day -15. Patients receive TMLI twice daily (BID) on days -8 to -5, fludarabine IV on days -4 to -2 and melphalan IV on day -2, followed by HCT on day 0. Patients receive GVHD prophylaxis with sirolimus and tacrolimus starting on day -1. Patients also undergo computed tomography (CT) during screening, nuclear scan and single photon emission computed tomography (SPECT) scans on study, bone marrow biopsy and aspiration, echocardiography, or multigated acquisition scan (MUGA), and blood sample collection during screening and throughout study.

After completion of study treatment, patients are followed up twice weekly for the first 100 days post-transplant, then twice monthly up to 6 months post-transplant followed by monthly until discontinuation of immunosuppressive therapy without evidence of GVHD with at least yearly follow-up for 2 years. ;

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• Syndrome

• NCT number: NCT06287944
• Study type: Interventional
• Source: City of Hope Medical Center
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: June 18, 2024
• Completion date: February 24, 2027