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

NCT ID: NCT06287944

Last Updated: 2025-07-29

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-01
• Study Completion Date: 2028-05-19

Brief 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.

Detailed 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.

Conditions

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Myelodysplastic Syndrome

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Patients receive daratumumab 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 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 CT during screening, nuclear scan and SPECT scans on study, bone marrow biopsy and aspiration, echocardiography, or MUGA, and blood sample collection during screening and throughout study.

Group Type: EXPERIMENTAL

Actinium Ac 225-DOTA-Daratumumab

Intervention Type: BIOLOGICAL

Given IV

Biospecimen Collection

Intervention Type: PROCEDURE

Undergo blood sample collection

Bone Marrow Aspiration

Intervention Type: PROCEDURE

Undergo bone marrow biopsy and aspiration

Bone Marrow Biopsy

Intervention Type: PROCEDURE

Undergo bone marrow biopsy and aspiration

Computed Tomography

Intervention Type: PROCEDURE

Undergo CT

Daratumumab

Intervention Type: BIOLOGICAL

Given IV

Echocardiography

Intervention Type: PROCEDURE

Undergo echocardiography

Fludarabine

Intervention Type: DRUG

Given IV

Hematopoietic Cell Transplantation

Intervention Type: PROCEDURE

Undergo SCT

Indium In 111-DOTA-Daratumumab

Intervention Type: BIOLOGICAL

Given IV

Melphalan

Intervention Type: DRUG

Given IV

Multigated Acquisition Scan

Intervention Type: PROCEDURE

Undergo MUGA

Radionuclide Imaging

Intervention Type: PROCEDURE

Undergo nuclear scan

Single Photon Emission Computed Tomography

Intervention Type: PROCEDURE

Undergo SPECT scan

Sirolimus

Intervention Type: DRUG

Given sirolimus

Tacrolimus

Intervention Type: DRUG

Given tacrolimus

Total Marrow and Lymphoid Irradiation

Intervention Type: RADIATION

Undergo TMLI

Interventions

Actinium Ac 225-DOTA-Daratumumab

Given IV

Intervention Type: BIOLOGICAL

Biospecimen Collection

Undergo blood sample collection

Intervention Type: PROCEDURE

Bone Marrow Aspiration

Undergo bone marrow biopsy and aspiration

Intervention Type: PROCEDURE

Bone Marrow Biopsy

Undergo bone marrow biopsy and aspiration

Intervention Type: PROCEDURE

Computed Tomography

Undergo CT

Intervention Type: PROCEDURE

Daratumumab

Given IV

Intervention Type: BIOLOGICAL

Echocardiography

Undergo echocardiography

Intervention Type: PROCEDURE

Fludarabine

Given IV

Intervention Type: DRUG

Hematopoietic Cell Transplantation

Undergo SCT

Intervention Type: PROCEDURE

Indium In 111-DOTA-Daratumumab

Given IV

Intervention Type: BIOLOGICAL

Melphalan

Given IV

Intervention Type: DRUG

Multigated Acquisition Scan

Undergo MUGA

Intervention Type: PROCEDURE

Radionuclide Imaging

Undergo nuclear scan

Intervention Type: PROCEDURE

Single Photon Emission Computed Tomography

Undergo SPECT scan

Intervention Type: PROCEDURE

Sirolimus

Given sirolimus

Intervention Type: DRUG

Tacrolimus

Given tacrolimus

Intervention Type: DRUG

Total Marrow and Lymphoid Irradiation

Undergo TMLI

Intervention Type: RADIATION

Other Intervention Names

225Ac-DOTA-Daratumumab; [225Ac]-DOTA-Daratumumab; Biological Sample Collection; Biospecimen Collected; Specimen Collection; Biopsy of Bone Marrow; Biopsy, Bone Marrow; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized axial tomography (procedure); Computerized Tomography; CT; CT Scan; tomography; Daratumumab Biosimilar HLX15; Daratumumab-fihj; Darzalex; HLX15; HuMax-CD38; JNJ-54767414; EC; Fluradosa; HCT; Hematopoietic Stem Cell Infusion; Hematopoietic Stem Cell Transplantation; HSCT; SCT; Stem Cell Transplant; stem cell transplantation; Stem Cell Transplantation, NOS; 111In-DOTA-Daratumumab; [111In]-DOTA-Daratumumab; Alanine Nitrogen Mustard; CB-3025; L-PAM; L-Phenylalanine Mustard; L-Sarcolysin; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; Gated Heart Pool Scan; MUGA; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; NM; Nuclear Medicine; nuclear medicine scan; radioimaging; Radionuclide Scanning; Scan; Scintigraphy; Medical Imaging, Single Photon Emission Computed Tomography; Single Photon Emission Tomography; Single-Photon Emission Computed; single-photon emission computed tomography; SPECT; SPECT imaging; SPECT SCAN; SPET; ST; tomography, emission computed, single photon; Tomography, Emission-Computed, Single-Photon; AY 22989; RAPA; Rapamune; Rapamycin; SILA 9268A; WY-090217; FK 506; FK-506; Fujimycin; Hecoria; Prograf; Protopic; Tacforius; TMLI

Eligibility Criteria

Inclusion Criteria

• Documented informed consent of the participant and/or legally authorized representative

• Assent, when appropriate, will be obtained per institutional guidelines
• ≥ 60 years. Note: Patients ≥ 18 years and < 60 years with HCT-comorbidity index (CI) ≥ 2 are also included
• Karnofsky performance status ≥ 70
• Eligible patients will have a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories :

• Acute myelogenous leukemia:

• Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5,5q-,-7,7q-,11q23-non t(9;11), inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (≥ 3 unrelated abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ disease, OR
• Patients with a complete morphological remission (CR) with minimal residual disease (MRD)-positive status by flow cytometry (≥ 0.1% by flow cytometry) or cytogenetic after at least 2 prior induction therapies, OR
• Patients with chemosensitive active disease defined as at least 50% reduction in their blast count after last treatment
• Myelodysplastic syndrome in high-intermediate (int-2) and high-risk categories per Revised International Prognostic Scoring System- (IPSS-R)
• Acute lymphocytic leukemia

• Patients with de novo or secondary disease according to NCCN guidelines for ALL hypoploidy (< 44 chromosomes); t(v;11q23): MLL rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (≥ 30,000 for B lineage or ≥ 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p, OR
• Patients with a complete response (CR) with MRD-positive status by flow cytometry (≥ 0.1% by flow cytometry) or cytogenetics after at least 2 prior induction therapies, OR
• Patients with chemosensitive active disease defined as at least 50% reduction in their blast count after last treatment
• A pretreatment measured creatinine clearance (absolute value) of ≥ 60 ml/minute (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Patients must have a serum bilirubin ≤ 2.0 mg/dl (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Patients must have a serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times the institutional upper limits of normal (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Patients must have a serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 times the institutional upper limits of normal (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) ≥ 50% (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Diffusion capacity of the lung for carbon monoxide (DLCO) > 50% predicted (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Forced expiratory volume in 1 second (FEV1) > 50% predicted (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy

• Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
• DONOR SPECIFIC CRITERIA: All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, and DR) identical sibling who is willing to donate mobilized peripheral blood stem cells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele matched unrelated donor. DQ or DP mismatch is allowed per discretion of the principal investigator. City of Hope (COH) standards of practice (SOP) (B.001.11) will be used for allogeneic donor evaluation, selection, and consent. Donor screening will be in compliance with all requirements of Food and Drug Administration (FDA) regulation 21 CFR Part 1271 including donor screening for COVID-19 exposure or infection

Exclusion Criteria

• Patients who had a prior allogeneic transplant
• All patients with prior radiation treatment to the lung, liver, and kidney
• Patients who have received prior radiopharmaceutical therapy
• Inclusion of other patients with previous radiation exposure will be determined based on the radiation oncologist medical doctor (MD) principal investigator (PI) evaluation and judgement
• For patients with leukemia or MDS: Patients may not have received more than 3 prior regimens, where the regimen intent was to induce remission
• Receiving any other investigational agents or concurrent biological, intensive chemotherapy or radiation therapy for the previous 2 weeks from conditioning
• Patients should have discontinued all previous intensive therapy, chemotherapy, or radiotherapy for 2 weeks prior to commencing therapy on this study. Note: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted. These include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs). FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Patients with other active malignancies are ineligible for this study, other than non-melanoma skin cancers
• Patients should not have any uncontrolled illness including ongoing or active bacterial, viral or fungal infection
• The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the investigator (treating physician) would place the recipient at unacceptable risk
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

City of Hope Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jeffrey Y Wong

Role: PRINCIPAL_INVESTIGATOR

City of Hope Medical Center

Locations

City of Hope Medical Center

Duarte, California, United States

Site Status: RECRUITING

Countries

United States

Facility Contacts

Jeffrey Y. Wong

Role: primary

jwong@coh.org

626-218-2247

Other Identifiers

NCI-2024-01131

Identifier Type: REGISTRY

Identifier Source: secondary_id

23694

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

23694

Identifier Type: -

Identifier Source: org_study_id