Radioimmunotherapy Conditioning With 131I- Apamistamab for Allogeneic Transplant in Relapse/Refractory AML

An Adaptive, Operationally Seamless Phase II / III Study of 131I-apamistamab-Led Allogeneic Hematopoietic Stem Cell Transplant in Patients With Relapsed or Refractory Acute Myeloid Leukemia With Active Disease

This is a multicenter, open-label study in people aged 18 and older with relapsed or refractory acute myeloid leukemia. It has two parts. In Phase 2, we are testing three radiation dose levels of 131I-apamistamab combined with fludarabine and low-dose whole-body radiation before stem cell transplant to find the safest and most effective dose. In Phase 3, patients will be randomly assigned to receive either this treatment combination or a standard of care regimen before transplant. The main goal is to see if the new approach helps people live longer. Phase 2 will enroll about 60 people, and Phase 3 will enroll about 246 people.

This trial consists of a Phase 2 randomized dose optimization component and a Phase 3 randomized, controlled two-arm component. This is a multicenter, open-label, study of 131I-apamistamab, fludarabine and TBI, which will be compared to standard of care regimen prior to HSCT in the Phase 3 portion, in subjects, aged 18 years old or greater, with active, relapsed or refractory AML. Active, relapsed or refractory AML is defined as any one of the following: (1) primary induction failure (PIF) after 2 or more cycles of therapy, or (2) first early relapse after a remission duration of fewer than 6 months, or (3) relapse refractory to salvage combination therapy, or (4) second or subsequent relapse.

All subjects will undergo screening prior to randomization in the study. Screening will include collection of informed consent, physical examination, review of inclusion/exclusion criteria with associated testing, summarizing documented history of AML and any other malignant disease, and identification and medical clearance of an appropriate allogeneic hematopoietic stem cell (HSC) donor.

Subjects must have active R/R AML with 5-20% blasts in marrow, documented CD45 expression, ≥18 years of age, not suitable for a myeloablative conditioning regimen, Karnofsky ≥70, and a medically cleared 8/8 matched HSC donor. Key exclusions include >20% marrow blasts, prior HSCT, prior maximal organ radiation, active CNS leukemia, significant cardiac disease, abnormal QTcF >450 ms, uncontrolled infection, or active malignancy within 2 years

Inclusion Criteria:

1. Have active, relapsed, or refractory AML with ≥5% and ≤20% blasts in the marrow.
2. 2R/R AML is defined as one of the following: Primary induction failure after ≥2 cycles of therapy, first early relapse after remission <6 months, relapse refractory to salvage combination therapy or second or subsequent relapse
3. Documented CD45 expression by leukemic cells via flow cytometry.
4. ≥18 years of age and not suitable for myeloablative conditioning regimen.
5. Circulating blast count <10,000/mm³ (hydroxyurea allowed).
6. Calculated creatinine clearance (Cockcroft-Gault) >50 mL/min.
7. Adequate hepatic function: AST/ALT ≤2 × ULN; total bilirubin ≤1.5 × ULN (≤3 × ULN if due to underlying malignancy or Gilbert's).
8. Karnofsky performance score ≥70.
9. Expected survival >60 days.
10. Central venous catheter line in place before study treatment.
11. 8/8 HLA-matched related or unrelated donor (HLA-A, HLA-B, HLA-C, DRB1).
12. Women of childbearing potential must be surgically sterile or use acceptable contraception through 1-year post-transplant.
13. Men with partners of childbearing potential must be surgically sterile or use acceptable contraception through 12 weeks after last dose.
14. Able to understand procedures, provide informed consent, and comply with study requirements.

Exclusion Criteria:

1. Positive human anti-mouse antibody (HAMA) at screening.
2. >20% leukemic blasts in marrow.
3. Prior radiation to maximally tolerated levels of any critical organ.
4. Active CNS leukemia (blasts in CSF or CNS chloromas).
5. Prior allogeneic or autologous HSCT.
6. Candidates suitable for myeloablative conditioning.
7. Clinically significant cardiac disease, including: NYHA Class III or IV heart failure, Clinically significant arrhythmias (ventricular tachycardia, ventricular fibrillation, Torsade de Pointes), Myocardial infarction with uncontrolled angina within 6 months, Clinically significant congestive heart failure or cardiomyopathy
8. QTcF >450 ms after correction of electrolytes (unless paced rhythm or investigator deems eligible; cardiology consult optional).
9. Positive HIV, HBV, or HCV test (exceptions: vaccinated HBV, or positive hepatitis markers with adequate organ function).
10. Active, uncontrolled infection.
11. Acute promyelocytic leukemia (t[15;17]).
12. Active malignancy within 2 years, except: Myelodysplastic syndrome, Treated non-melanoma skin cancer, Completely resected stage 0-1 melanoma (>1 year from resection), Carcinoma in situ or cervical intraepithelial neoplasia, Organ-confined prostate cancer without progression
13. Inability to tolerate diagnostic or therapeutic procedures, particularly radiation isolation.
14. Received anti-leukemic therapy within 14 days prior to randomization (hydroxyurea allowed up to day of 131I-apamistamab).