Clinical trial NCT06287944: 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2024-03-01
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Incidence of adverse events (CTCAE)
timeFrame: Up to 2 years post-transplant
measure: Incidence of adverse events (Bearman)
timeFrame: Up to 2 years post-transplant
measure: Dose limiting toxicity (DLT)
timeFrame: Up to 30 days post-stem cell infusion
measure: Maximum tolerated dose/recommended phase II dose (MTD/RP2D)
timeFrame: Up to 30 days post stem cell infusion
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: At start of protocol therapy to death or last follow-up up to 2 years post transplant
measure: Event-free survival (EFS)
timeFrame: At start of protocol therapy to death, relapse/progression or last follow-up up to 2 years post-transplant
measure: Cumulative incidence of relapse/progression (CIR)
timeFrame: At start of therapy up to 2 years post transplant
measure: Graft versus host disease and relapse free survival (GRFS)
timeFrame: At start of therapy up to 2 years post-transplant
measure: Complete remission (CR) proportion
timeFrame: At start of therapy up to day 30
measure: Non-relapse mortality (NRM)
timeFrame: At start of therapy until non-disease related death or last follow-up up to 2 years post-transplant
measure: Incidence of infection
timeFrame: At day 0 up to 100 days post-transplant
measure: Neutrophil recovery rate
timeFrame: At stem cell infusion up to the first to three consecutive days with neutrophil count greater than 0.5 x 10^9/L up to 2 years post-transplant
measure: Incidence of grade 2-4 and 3-4 acute graft-versus-host disease (GVHD)
timeFrame: At date of stem cell infusion to document/biopsy proven acute GVHS onset (within first 100 days post-transplant)
measure: Incidence of chronic GVHD (cGVHD)
timeFrame: At 80-100 days post-transplant to documented/biopsy proven cGVHD onset date up to 2 years post-transplant
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
Study officials:
affiliation: City of Hope Medical Center
name: Jeffrey Y Wong
role: PRINCIPAL_INVESTIGATOR
References: