The study is a multicenter, open label Phase I/II trial. 1. To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax and azacitidine for patients with CD33 positive AML. (Phase I portion) 2. To assess the percentage of patients with CR, CRh, CRi, MLFS or Overall Response (CR + CRh + CRi + MLFS), up to 6 months after the start of treatment without receiving other AML therapies.. (Phase 2 portion)
The study is a multicenter, open label Phase I and Phase II trial combining lintuzumab-Ac225 with venetoclax and azacitidine in patients who have relapsed or refractory AML. The Phase I portion is a dose-finding study which will enroll at least three patients at each dose level. Patients in each dose level will be observed for a minimum of 4 weeks before dose escalation occurs. There is no dose escalation for any individual patient. Lintuzumab-Ac225 is administered on Day 8 of the first 4 treatment cycles. The Phase II portion of the study will enroll patients at the MTD dose level of lintuzumab-Ac225 as determined in the Phase I portion of the study. The goal of the Phase II portion will be to further characterize the safety and efficacy of the MTD dose of lintuzumab-Ac225.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
In the Phase I, patients will be enrolled into the following dose escalation cohorts: 0.50 μCi/kg, 1.0 μCi/kg, and 1.5 μCi/kg. If the 0.50 μCi/kg dose is determined to exceed the MTD, a 0.25 μCi/kg dose will be explored.
400 mg daily will be taken orally on Days 1-21 of a 28-day cycle. There will be a ramp up of venetoclax dosing in the first cycle, with 100 mg administered on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and Day 4 and later. Patients on antifungal azoles should receive one-half these doses, up to a maximum of 200 mg of venetoclax.
75 mg/m2 will be administered on days 1-7 of a 28-day cycle.
Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225
To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax and azacitidine for patients with CD33 positive AML
Time frame: Cycle 1, up to 48 days
Phase II: Overall Response (CR + CRh + CRi + MLFS)
To assess the percentage of patients achieving CR, CRh, CRi, morphologic leukemia-free state (MLFS), or Overall Response (CR + CRh + CRi + MLFS), up to 6 months after the start of treatment without receiving other AML therapies
Time frame: Up to 6 months
Phase I: Overall Response
Number of patients who's overall response is CR or CRh or CRi or MLFS
Time frame: Up to 6 months
Phase I: OS
Number of patients who died
Time frame: Phase I: End of 6 months, 12 months, 24 months.
Phase II: OS
Number of patients who died
Time frame: Phase II: End of 6 months, 12 months, 24 months
Phase I and II: DFS
Disease-free survival
Time frame: Through study completion, up to 2 years
Phase I and II: Evaluate incidence of AEs and SAEs
Rate of AEs and SAEs, including infusion-related reactions
Time frame: Through study completion, up to 2 years
Phase I and II: Lab abnormalities (other than hematologic indices)
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Summary of rate of Grade 3/4 lab abnormalities
Time frame: Through study completion, up to 2 years
Phase I and II: Evaluate BH3 priming assay results
Summary of assay results
Time frame: Completion of Cycle 1, estimated 1 month
Phase I and II: MRD status
Number of patients who are MRD negative
Time frame: From date of first dose until the date of first documented response, first assessment at 6 months