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
ID: NCT06287944
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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.
Read Full Scientific Objectives & Methods
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.
Given IV
Undergo blood sample collection
Undergo bone marrow biopsy and aspiration
Undergo bone marrow biopsy and aspiration
Undergo CT
Given IV
Undergo echocardiography
Given IV
Undergo SCT
Given IV
Given IV
Undergo MUGA
Undergo nuclear scan
Undergo SPECT scan
Given sirolimus
Given tacrolimus
Undergo TMLI
Treatment Arms Description
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.
- Documented informed consent of the participant and/or legally authorized representative
- Assent, when appropriate, will be obtained per institutional guidelines
- ≥ 70 years. Note: Patients ≥ 18 years and \< 70 years with active, relapsed or refractory, or high-risk acute leukemia or MDS as defined below.
- 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
- Evidence of CD38 expression by flow cytometry AND one of the below
- 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 25% reduction in their blast count after last treatment
- Patients with myelofibrosis (primary or secondary, including post-polycythemia vera and post-essential thrombocythemia myelofibrosis) may be eligible for enrollment if they meet criteria for high-risk disease and are planned for allogeneic hematopoietic cell transplantation.
- Eligible patients include those with:
- Accelerated-phase or blast-phase myelofibrosis, defined as 10% to 19% blasts or ≥20% blasts, respectively, in peripheral blood or bone marrow
- High-risk chronic-phase primary or secondary myelofibrosis, defined as disease meeting transplant-appropriate risk criteria by a validated MF prognostic model, including DIPSS intermediate-2 or high-risk; DIPSS-plus intermediate-2 or high-risk; MIPSS70 intermediate, high, or very high-risk; MIPSS70-plus or MIPSS70-plus version 2.0 intermediate, high, or very high-risk; GIPSS intermediate-2 or high-risk; or MYSEC-PM intermediate-2 or high-risk for post-polycythemia vera or post-essential thrombocythemia myelofibrosis. Patients may also qualify based on adverse clinical, cytogenetic, or molecular features supporting high-risk disease biology and transplant candidacy, including complex karyotype, monosomal karyotype, very high-risk karyotype, high molecular risk mutations, transfusion-dependent anemia, thrombocytopenia, circulating blasts, constitutional symptoms, or symptomatic splenomegaly despite standard therapy
- Suboptimal response, progression, or intolerance to prior JAK inhibitor therapy, defined as failure to achieve adequate spleen or symptom response after an appropriate trial of therapy, generally at least 12 weeks at an appropriate or maximally tolerated dose when clinically feasible; loss of prior spleen or symptom response; worsening splenomegaly; persistent or worsening constitutional symptoms attributable to MF; worsening cytopenias or transfusion dependence; progression to accelerated-phase or blast-phase disease; emergence of adverse cytogenetic or molecular features; or inability to continue JAK inhibitor therapy due to treatment-related toxicity. A minimum duration of JAK inhibitor exposure is not required when the treating investigator determines that continued therapy is not clinically appropriate due to rapidly progressive disease, accelerated-phase or blast-phase transformation, clinically significant cytopenias, intolerance, or urgent need to proceed to allogeneic HCT. The rationale for early determination of JAK inhibitor failure or inability to continue JAK inhibitor therapy will be documented in the medical record.
- Persistent disease burden, including persistent splenomegaly, circulating or marrow blasts, transfusion dependence, cytopenias attributable to MF, leukocytosis, thrombocytopenia, adverse cytogenetic or molecular features, extramedullary hematopoiesis, or progression despite standard therapy, may support high-risk classification but does not constitute a separate eligibility criterion unless the patient also meets the defined advanced-phase, validated risk-model, or JAK inhibitor failure criteria above.
- \*\*See Appendix F: Defined Risk Scoring Systems in MF
- All patients must demonstrate CD38 expression on disease-relevant cell populations (bone marrow and/or peripheral blood) as assessed by flow cytometry or an equivalent validated assay prior to enrollment.
- Clinical Laboratory and Organ Function Criteria (To be performed within 30 days prior to Day 1 of protocol therapy unless otherwise stated) or (acceptable windows for tests are indicated in the Study Calendar Section 10.0).
- 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
- Patients who had a prior allogeneic transplant
- Patients who have had prior radiotherapy
- Patients who have received prior radiopharmaceutical therapy
- 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 Outcome Measures
- Incidence of adverse events (CTCAE) — Time Frame: Up to 2 years post-transplant
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.
- Incidence of adverse events (Bearman) — Time Frame: Up to 2 years post-transplant
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.
- Dose limiting toxicity (DLT) — Time Frame: Up to 30 days post-stem cell infusion
DLT will be graded using the NCI CTCAE v5 scale.
- Maximum tolerated dose/recommended phase II dose (MTD/RP2D) — Time Frame: Up to 30 days post stem cell infusion
MTD/RP2D will be defined as the highest dose where 6 patients have been treated and at most on patient experiences a DLT.
View Secondary Outcome Measures (10)
- Overall survival (OS) — Time Frame: At start of protocol therapy to death or last follow-up up to 2 years post transplant
OS will be defined as the time from start of protocol therapy to death or last follow-up whichever comes first. OS will be calculated using the Kaplan-Meier method.
- Event-free survival (EFS) — Time Frame: At start of protocol therapy to death, relapse/progression or last follow-up up to 2 years post-transplant
EFS will be defined as the time from start of protocol therapy to death, relapse/progression or last follow-up, whichever comes first. EFS will be calculated using the Kaplan-Meier method.
- Cumulative incidence of relapse/progression (CIR) — Time Frame: At start of therapy up to 2 years post transplant
CIR will be measured from start of therapy. Death without relapse/progression is considered a competing risk.
- Graft versus host disease and relapse free survival (GRFS) — Time Frame: At start of therapy up to 2 years post-transplant
GRFS will be measured from the start of therapy. GRFS will be calculated using the Kaplan-Meier method.
- Complete remission (CR) proportion — Time Frame: At start of therapy up to day 30
CR will be defined as the time from start of therapy to the time of biopsy proven CR.
- Non-relapse mortality (NRM) — Time Frame: At start of therapy until non-disease related death or last follow-up up to 2 years post-transplant
NRM will be defined as the time from start of therapy until non-disease related death, or last follow-up, whichever comes first. NRM will be calculated as competing risks.
- Incidence of infection — Time Frame: At day 0 up to 100 days post-transplant
Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any.
- Neutrophil recovery rate — Time Frame: 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
Neutrophil recovery rate will be measured from stem cell infusion to the first to three consecutive days with neutrophil count greater than 0.5 x 10\^9/L.
- Incidence of grade 2-4 and 3-4 acute graft-versus-host disease (GVHD) — Time Frame: At date of stem cell infusion to document/biopsy proven acute GVHS onset (within first 100 days post-transplant)
Documented/biopsy proven acute GVHD will be graded according to the Consensus Grading. Acute GVHD will be measured from date of stem cell infusion to document/biopsy proven acute GVHD onset date (within the first 100 days post-transplant) and will be used to estimate the cumulative incidence. GVHD will be calculated as competing risks.
- Incidence of chronic GVHD (cGVHD) — Time Frame: At 80-100 days post-transplant to documented/biopsy proven cGVHD onset date up to 2 years post-transplant
Documented/biopsy proven cGVHD is scored according to National Institutes of Health Consensus Staging. CGVHD is measured from approximately 80-100 days post-transplant to the documented/biopsy proven cGVHD onset date and will be used to estimate the cumulative incidence. The incidence of cGVHD will be calculated as competing risks.
This trial is recruiting at 1 study facilities worldwide. Click below to see if there is a clinic or hospital in your area:
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View Official Medical/Scientific 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