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

NCT06287944 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 23694NCI-2024-01131P30CA033572
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (4)

• Incidence of adverse events (CTCAE)

  Toxicity will be scored on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 scale. Toxicity will be recorded in each patient and will include the type, severity, and probable association with the study regimen.

  Up to 2 years post-transplant

• Incidence of adverse events (Bearman)

  Toxicity will be scored on the Bearman Scale. Toxicity will be recorded in each patient and will include the type, severity, and probable association with the study regimen.

  Up to 2 years post-transplant

• Dose limiting toxicity (DLT)

  DLT will be graded using the NCI CTCAE v5 scale.

  Up to 30 days post-stem cell infusion

• Maximum tolerated dose/recommended phase II dose (MTD/RP2D)

  MTD/RP2D will be defined as the highest dose where 6 patients have been treated and at most on patient experiences a DLT.

  Up to 30 days post stem cell infusion

Secondary Outcomes (10)

• Overall survival (OS)

  At start of protocol therapy to death or last follow-up up to 2 years post transplant

• Event-free survival (EFS)

  At start of protocol therapy to death, relapse/progression or last follow-up up to 2 years post-transplant

• Cumulative incidence of relapse/progression (CIR)

  At start of therapy up to 2 years post transplant

• Graft versus host disease and relapse free survival (GRFS)

  At start of therapy up to 2 years post-transplant

• Complete remission (CR) proportion

  At start of therapy up to day 30

Study Arms (1)

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

EXPERIMENTAL

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.

Biological: Actinium Ac 225-DOTA-Daratumumab; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Biological: Daratumumab; Procedure: Echocardiography; Drug: Fludarabine; Procedure: Hematopoietic Cell Transplantation; Biological: Indium In 111-DOTA-Daratumumab; Drug: Melphalan; Procedure: Multigated Acquisition Scan; Procedure: Radionuclide Imaging; Procedure: Single Photon Emission Computed Tomography; Drug: Sirolimus; Drug: Tacrolimus; Radiation: Total Marrow and Lymphoid Irradiation

Interventions

Actinium Ac 225-DOTA-Daratumumab BIOLOGICAL

Given IV

Also known as: 225Ac-DOTA-Daratumumab, [225Ac]-DOTA-Daratumumab

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow biopsy and aspiration

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy and aspiration

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, CT, CT Scan, tomography

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Daratumumab BIOLOGICAL

Given IV

Also known as: Daratumumab Biosimilar HLX15, Daratumumab-fihj, Darzalex, HLX15, HuMax-CD38, JNJ-54767414

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Echocardiography PROCEDURE

Undergo echocardiography

Also known as: EC

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Fludarabine DRUG

Given IV

Also known as: Fluradosa

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Hematopoietic Cell Transplantation PROCEDURE

Undergo SCT

Also known as: HCT, Hematopoietic Stem Cell Infusion, Hematopoietic Stem Cell Transplantation, HSCT, SCT, Stem Cell Transplant, stem cell transplantation, Stem Cell Transplantation, NOS

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Indium In 111-DOTA-Daratumumab BIOLOGICAL

Given IV

Also known as: 111In-DOTA-Daratumumab, [111In]-DOTA-Daratumumab

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Melphalan DRUG

Given IV

Also known as: 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

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: 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

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Radionuclide Imaging PROCEDURE

Undergo nuclear scan

Also known as: NM, Nuclear Medicine, nuclear medicine scan, radioimaging, Radionuclide Scanning, Scan, Scintigraphy

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Single Photon Emission Computed Tomography PROCEDURE

Undergo SPECT scan

Also known as: 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

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Sirolimus DRUG

Given sirolimus

Also known as: AY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Tacrolimus DRUG

Given tacrolimus

Also known as: FK 506, FK-506, Fujimycin, Hecoria, Prograf, Protopic, Tacforius

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Total Marrow and Lymphoid Irradiation RADIATION

Undergo TMLI

Also known as: TMLI

Treatment ( Actinium Ac 225-DOTA-Daratumumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

RECRUITING

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Specimen Handling; Biopsy; daratumumab; fludarabine; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Indium; Melphalan; Nuclear Medicine Department, Hospital; X-Rays; Photons; Sirolimus; Tacrolimus; Lymphatic Irradiation

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Metals, Heavy; Elements; Inorganic Chemicals; Metals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Hospital Administration; Health Facility Administration; Organization and Administration; Health Services Administration; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing; Elementary Particles; Light; Optical Phenomena; Radiation, Nonionizing; Macrolides; Lactones; Radiotherapy

Study Officials

• Jeffrey Y Wong

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 16, 2024
• First Posted: March 1, 2024
• Study Start: July 1, 2025
• Primary Completion (Estimated): May 19, 2028
• Study Completion (Estimated): May 19, 2028
• Last Updated: July 29, 2025

Record last verified: 2025-07

Locations

US (1)