Acute Leukemia, Myeloid Leukemia, Acute Myelogenous Leukemia, Acute Myeloid Leukemia, Acute Myeloid Leukemia, in Relapse, Myelogenous Leukemia, Myelogenous Leukemia, Acute, Myelogenous Leukemia in Relapse, Transplant-Related Disorder, Allogeneic Disease, Refractory AML
Conditions
Keywords
Acute Myeloid Leukemia, Leukemia, Acute Myeloid, Acute Bone Marrow Cell Transplant, Transplant, Bone Marrow HCT, Refractory AML, Relapsed AML, I-131, Iomab, I131- Apamistamab, Iodine, Iodine-131, 131-I AML, Iomab-B, Radioimmunotherapy, Allogeneic Transplant, Radiotherapy, CD45, Anti-CD45 antibody, Apamistamab, Fludarabine, Bone Marrow Transplant, Radiolabeled antibody therapy, 131I -apamistamab
Brief summary
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.
Detailed description
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
Interventions
DRUG131I-apamistamab
Iodine-131 radiolabeled anti-CD45 monoclonal antibody (apamistamab). Administered IV as a dosimetric dose followed by treatment dose.
DRUGFludarabine
Fludarabine phosphate, 30 mg/m² IV daily on Days -6 through -2.
DRUGCyclophosphamide
Cyclophosphamide
RADIATIONTotal Body Irradiation (TBI)
TBI, 200 cGy on Day -1 prior to HSCT.
Unmodified, G-CSF-mobilized donor stem cells infused on Day 0.
Sponsors
Actinium Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Adaptive, seamless Phase 2/3 design including Phase 2 randomized dose optimization followed by a Phase 3 randomized, controlled two-arm comparison of 131I-apamistamab conditioning versus control regimen.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) -Phase 3 | Up to 5 years post-randomization | Defined as time from randomization to death from any cause. Subjects without documented death at the time of analysis will be censored at the date of last known contact. |
| Incidence of Grade ≥4 Non-Hematologic Toxicity | Up to 6 months post-HSCT | Number and proportion of subjects developing grade ≥4 non-hematologic toxicities as graded by NCI CTCAE v5.0. |
| Complete Remission (CR) at Day 28 Post-HSCT - Phase 2 | Day 28 post-HSCT | Number of subjects achieving CR by Day 28 (±3 days) post-HSCT, based on bone marrow assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse-Free Survival (RFS) | 6 months post-HSCT and up to 5 years post-randomization | Probability of being alive without previous relapse of disease among subjects who achieve a post-transplant CR or CRi. |
| Event-Free Survival (EFS) | Up to 5 years post-randomization | Time from randomization to relapse, treatment failure, or death from any cause, whichever occurs first. |
| Overall Response Rate (ORR) | Day 28 post-HSCT and up to 12 months | Proportion of subjects achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) following transplant |
| Duration of Remission (DOR) | Up to 5 years post-randomization | Time from first documented CR or CRi until relapse or death from any cause. |
| GvHD-Free Relapse-Free Survival (GRFS) | Up to 5 years post-HSCT | Composite endpoint defined as time from HSCT to first event of grade III-IV acute GvHD, chronic GvHD requiring systemic therapy, relapse, or death. |
| Survival Rate at One and Two Years Post-Transplant | 1 year and 2 years post-HSCT | Proportion of subjects alive at one year and two years following HSCT. |
| Incidence of Acute and Chronic GvHD | 6 months post-HSCT | Number and proportion of subjects developing acute or chronic GvHD, summarized by severity. |
| Overall Survival | Up to 2 years post-enrollment | Time from enrollment to death from any cause. |
| Time to Engraftment | Up to Day 100 post-HSCT | Days from HSCT (Day 0) until subject reaches ≥95% donor cell engraftment. |
| Engraftment | Day 100 post-HSCT | Number of subjects achieving ≥95% donor cell engraftment by Day 100 post-HSCT. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Non-Relapse Mortality (NRM) | Up to 5 years post-randomization | Time to deaths without relapse/recurrence |
| QTc Interval Prolongation | Up to 12 months post-HSCT | Extended duration of the QT interval on an electrocardiogram |
| Incidence of Renal and Hepatic Toxicity | Up to 12 months post-HSCT | Number and proportion of subjects developing renal and hepatic toxicity, summarized by severity. |
| Rates of Engraftment and Graft Failure | Up to Day 100 post-HSCT | Rate evaluation of number of subjects achieving ≥95% donor cell engraftment or graft failure by Day 100 post-HSCT |
| Adverse Events of Special Interest | Up to 5 years post-randomization | Number and proportion of subjects of adverse events of special interest, summarized by severity. |
| Adverse Events Related to Study Treatment | Up to 5 years post-randomization | Number and proportion of subjects of adverse events due to study treatment, summarized by severity. |
| Minimal Residual Disease (MRD) Negativity Rate | Up to 12 months post-HSCT | Proportion of subjects achieving MRD negativity by multiparameter flow cytometry among those with CR/CRi. |
Contacts
Primary ContactMadhuri Vusirikala, MD
Outcome results
None listed