Trial Title:
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
Condition:
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Myelodysplastic Syndromes
Syndrome
Sirolimus
Fludarabine
Melphalan
Mechlorethamine
Daratumumab
Nitrogen Mustard Compounds
Tacrolimus
Antibodies, Monoclonal
1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Actinium Ac 225-DOTA-Daratumumab
Description:
Given IV
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
225Ac-DOTA-Daratumumab
Other name:
[225Ac]-DOTA-Daratumumab
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo bone marrow biopsy and aspiration
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo bone marrow biopsy and aspiration
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Biological
Intervention name:
Daratumumab
Description:
Given IV
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
Daratumumab Biosimilar HLX15
Other name:
Daratumumab-fihj
Other name:
Darzalex
Other name:
HLX15
Other name:
HuMax-CD38
Other name:
JNJ-54767414
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo echocardiography
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
EC
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Given IV
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
Fluradosa
Intervention type:
Procedure
Intervention name:
Hematopoietic Cell Transplantation
Description:
Undergo SCT
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
HCT
Other name:
Hematopoietic Stem Cell Infusion
Other name:
Hematopoietic Stem Cell Transplantation
Other name:
HSCT
Other name:
SCT
Other name:
Stem Cell Transplant
Other name:
stem cell transplantation
Other name:
Stem Cell Transplantation, NOS
Intervention type:
Biological
Intervention name:
Indium In 111-DOTA-Daratumumab
Description:
Given IV
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
111In-DOTA-Daratumumab
Other name:
[111In]-DOTA-Daratumumab
Intervention type:
Drug
Intervention name:
Melphalan
Description:
Given IV
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
Alanine Nitrogen Mustard
Other name:
CB-3025
Other name:
L-PAM
Other name:
L-Phenylalanine Mustard
Other name:
L-Sarcolysin
Other name:
L-Sarcolysin Phenylalanine mustard
Other name:
L-Sarcolysine
Other name:
Melphalanum
Other name:
Phenylalanine Mustard
Other name:
Phenylalanine Nitrogen Mustard
Other name:
Sarcoclorin
Other name:
Sarkolysin
Other name:
WR-19813
Intervention type:
Procedure
Intervention name:
Multigated Acquisition Scan
Description:
Undergo MUGA
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
Blood Pool Scan
Other name:
Equilibrium Radionuclide Angiography
Other name:
Gated Blood Pool Imaging
Other name:
Gated Heart Pool Scan
Other name:
MUGA
Other name:
MUGA Scan
Other name:
Multi-Gated Acquisition Scan
Other name:
Radionuclide Ventriculogram Scan
Other name:
Radionuclide Ventriculography
Other name:
RNVG
Other name:
SYMA Scanning
Other name:
Synchronized Multigated Acquisition Scanning
Intervention type:
Procedure
Intervention name:
Radionuclide Imaging
Description:
Undergo nuclear scan
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
NM
Other name:
Nuclear Medicine
Other name:
nuclear medicine scan
Other name:
radioimaging
Other name:
Radionuclide Scanning
Other name:
Scan
Other name:
Scintigraphy
Intervention type:
Procedure
Intervention name:
Single Photon Emission Computed Tomography
Description:
Undergo SPECT scan
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
Medical Imaging, Single Photon Emission Computed Tomography
Other name:
Single Photon Emission Tomography
Other name:
Single-Photon Emission Computed
Other name:
single-photon emission computed tomography
Other name:
SPECT
Other name:
SPECT imaging
Other name:
SPECT SCAN
Other name:
SPET
Other name:
ST
Other name:
tomography, emission computed, single photon
Other name:
Tomography, Emission-Computed, Single-Photon
Intervention type:
Drug
Intervention name:
Sirolimus
Description:
Given sirolimus
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
AY 22989
Other name:
RAPA
Other name:
Rapamune
Other name:
Rapamycin
Other name:
SILA 9268A
Other name:
WY-090217
Intervention type:
Drug
Intervention name:
Tacrolimus
Description:
Given tacrolimus
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
FK 506
Other name:
FK-506
Other name:
Fujimycin
Other name:
Hecoria
Other name:
Prograf
Other name:
Protopic
Other name:
Tacforius
Intervention type:
Radiation
Intervention name:
Total Marrow and Lymphoid Irradiation
Description:
Undergo TMLI
Arm group label:
Treatment ( Actinium Ac 225-DOTA-Daratumumab)
Other name:
TMLI
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.
Criteria for 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)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
City of Hope Medical Center
Address:
City:
Duarte
Zip:
91010
Country:
United States
Contact:
Last name:
Jeffrey Y. Wong
Phone:
626-218-2247
Email:
jwong@coh.org
Investigator:
Last name:
Jeffrey Y. Wong
Email:
Principal Investigator
Start date:
October 18, 2024
Completion date:
February 24, 2027
Lead sponsor:
Agency:
City of Hope Medical Center
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
City of Hope Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06287944