Venetoclax and Lintuzumab-Ac225 in AML Patients

Study Overview
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Brief Summary
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The study is a multicenter, open label Phase I/II trial. To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 added to venetoclax for patients with CD33 positive relapsed/refractory AML. (Phase 1 portion) To assess the percentage of patients with CR, CRh, or Overall Response (CR + CRh), up to 6 months after the start of treatment without receiving other AML therapies. (Phase 2 portion)

Detailed Description
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The study is a multicenter, open label Phase I and Phase II trial combining lintuzumab-Ac225 with venetoclax 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 a dose level will be observed for a minimum of 4 weeks before dose escalation occurs. There is no dose escalation for any individual patient. 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.

Official Title
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A Phase I/II Study of Venetoclax and Lintuzumab-Ac225 in Patients With Refractory or Relapsed AML

Conditions
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Acute Myeloid Leukemia, Relapsed Adult AML

Intervention / Treatment
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* Biological: Lintuzumab-Ac225
* Drug: Venetoclax
* Drug: Spironolactone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Refractory or relapsed AML which will include: Refractory disease will be defined as at least 1 prior treatment with no remission. Relapsed disease will be defined as 5% or more blasts in bone marrow seen after remission. Patients with AML arising from myelodysplastic syndromes (including CMML) or myeloproliferative neoplasms (secondary AML, ts-AML) are also eligible. Circulating blast count ≤ 200/μL within 10 days prior to first cycle of treatment. Hydroxyurea should be used to keep the peripheral blast count ≤ 200/μL until the first day of protocol treatment, to the extent that this is possible ECOG ≤ 2 Estimated creatinine clearance ≥ 50 mL/min AST and ALT ≤ 3.0 x ULN Bilirubin ≤ 3.0 x ULN Exclusion Criteria: Active CNS Leukemia. Known HIV infection or known hepatitis B or hepatitis C infection (with a detectable viral load). Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment. Secondary refractory AML (e.g., treated for current relapse without achieving remission); a. With the exception that single agent FLT3 inhibitors, IDH1/IDH2 inhibitors are allowed for current relapse without achieving remission. Have received prior radiation to maximally tolerated levels to any critical normal organ. Clinically significant cardiac disease. Active, uncontrolled serious infection. Have other non-myeloid malignancy within 2 years of entry (with exceptions). Psychiatric disorder that would preclude study participation Previous solid organ transplant (prior treatment with SCT is allowed but not if patient has GVHD or is still receiving immunosuppression/GVHD therapy).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I and Phase II<br>Lintuzumab-Ac225 administered on Day 5 of each cycle for four cycles (unless in the 0.5 μCi/kg or 0.25 μCi/kg cohorts, where there is a potential for an additional four cycles, pending PI and Medical Monitor review). Venetoclax taken on Days 1-21 of each cycle for up to 12 cycles. Each cycle is 28 days, with a potential to expand to 42 days to allow for full hematologic recovery. | Biological: Lintuzumab-Ac225<br>* 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.<br>* Other names: Actimab;Drug: Venetoclax<br>* 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.<br>* Other names: Venclexta;Drug: Spironolactone<br>* 25 mg by mouth daily, administered on Cycle 1 Day 15 and continued for 12 months after the subject's last treatment with lintuzumab-Ac225.<br>* Other names: Aldactone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225 | To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 added to venetoclax for patients with CD33 positive relapse/refractory AML. | Cycle 1, up to 48 days | 
| Phase II: Overall Response (CR + CRh + CRi) | To assess the percentage of patients with CR, CRh, CRi or Overall Response (CR + CRh + CRi), up to 6 months after the start of treatment without receiving other AML therapies. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Overall Response | Number of patients who's overall response is CR, CRh, or CRi | Up to 6 months | 
| Phase I and II: OS | Number of patients who died | End of 6 months, 12 months, 2 years | 
| Phase I and II: DFS | Disease-free survival | End of 6 months, 12 months, 2 years | 
| Phase I and II: Evaluate incidence of AEs and SAEs | Rate of AEs and SAEs, including infusion-related reactions | Through study completion, up to 2 years | 
| Phase I and II: Evaluate BH3 priming assay results | Summary of assay results | Completion of Cycle 1, estimated 1 month | 
| Phase I and II: MRD status | Number of patients who are MRD negative | From date of first dose until the date of first documented response, first assessment at 6 months | 
| Phase I and II: Lab abnormalities (other than hematologic indices) | Summary of rate of Grade 3/4 lab abnormalities | Through study completion, up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lintuzumab-Ac225, Venetoclax, Lintuzumab, Refractory AML