Venetoclax, Azacitidine, and Lintuzumab-Ac225 in AML Patients

Study Overview
=================
Brief Summary
-----------------
The study is a multicenter, open label Phase I/II trial. 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) 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)

Detailed Description
-----------------
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.

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

Conditions
-----------------
Acute Myeloid Leukemia, Relapsed Adult AML

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed acute myeloid leukemia 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. White blood cell (WBC) count < 10 x 109/L; a. Use of hydroxyurea, prior to Cycle 1 and during Cycles 1 and 2, is permitted to lower the WBC count in the peripheral blood. Age > 18 years. Estimated creatinine clearance ≥ 50 mL/min calculated by the Cockroft-Gault formula. AST and ALT ≤ 3.0 x ULN (unless considered to be due to leukemic organ involvement). Bilirubin ≤ 3.0 x ULN (unless considered to be due to leukemic organ involvement). Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2. Exclusion Criteria: Have acute promyelocytic leukemia (APL). Active CNS leukemia. Patients with symptoms of CNS involvement, particularly those with M4 or M5 subtypes, should undergo lumbar puncture prior to treatment on study to exclude CNS disease. Symptoms include cranial neuropathies, other neurologic deficits, and headache. Have received prior radiation to maximally tolerated levels to any critical normal organ. Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment. 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 as GVHD or is still receiving immunosuppression/GVHD therapy).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 will be administered on Day 8 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 will be taken on Days 1-21 of each cycle for up to 12 cycles. Azacitidine will be administered on Days 1-7 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: Azacitidine<br>* 75 mg/m2 will be administered on days 1-7 of a 28-day cycle.<br>* Other names: Vidaza;|

What is the study measuring?
-----------------
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 when given in combination with venetoclax and azacitidine for patients with CD33 positive AML | 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 | 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 or CRh or CRi or MLFS | Up to 6 months | 
| Phase I: OS | Number of patients who died | Phase I: End of 6 months, 12 months, 24 months. | 
| Phase II: OS | Number of patients who died | Phase II: End of 6 months, 12 months, 24 months | 
| Phase I and II: DFS | Disease-free survival | 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 | Through study completion, up to 2 years | 
| 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 | 
| 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 | 

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