Venetoclax, Azacitidine, and Lintuzumab-Ac225 in AML Patients

Phase 1

Withdrawn

• Conditions: Relapsed Adult AML; Acute Myeloid Leukemia
• Interventions: Biological: Lintuzumab-Ac225; Drug: Venetoclax; Drug: Azacitidine

• Registration Number: NCT03932318
• Lead Sponsor: Actinium Pharmaceuticals

Brief Summary

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)

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.

Study Timeline

• Study First Submitted: 2019-04-17
• Study First Submitted QC: 2019-04-29
• Study First Posted: 2019-04-30
• Study Start: 2023-03
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-19
• Last Update Posted: 2023-07-20
• Primary Completion: 2023-12
• Study Completion: 2024-09

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Histologically confirmed acute myeloid leukemia

2. Refractory or relapsed AML which will include:

   1. Refractory disease will be defined as at least 1 prior treatment with no remission.
   2. Relapsed disease will be defined as 5% or more blasts in bone marrow seen after remission.
   3. Patients with AML arising from myelodysplastic syndromes (including CMML) or myeloproliferative neoplasms (secondary AML, ts-AML) are also eligible.

3. 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.

4. Age > 18 years.

5. Estimated creatinine clearance ≥ 50 mL/min calculated by the Cockroft-Gault formula.

6. AST and ALT ≤ 3.0 x ULN (unless considered to be due to leukemic organ involvement).

7. Bilirubin ≤ 3.0 x ULN (unless considered to be due to leukemic organ involvement).

8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.

Exclusion Criteria

1. Have acute promyelocytic leukemia (APL).
2. 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.
3. Have received prior radiation to maximally tolerated levels to any critical normal organ.
4. Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
5. Clinically significant cardiac disease.
6. Active, uncontrolled serious infection.
7. Have other non-myeloid malignancy within 2 years of entry (with exceptions).
8. Psychiatric disorder that would preclude study participation
9. Previous solid organ transplant (prior treatment with SCT is allowed but not if patient as GVHD or is still receiving immunosuppression/GVHD therapy).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I and Phase II	Lintuzumab-Ac225	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.
Phase I and Phase II	Venetoclax	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.
Phase I and Phase II	Azacitidine	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.

Primary Outcome Measures

Name	Time	Method
Phase II: Overall Response (CR + CRh + CRi + MLFS)	Up to 6 months	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
Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225	Cycle 1, up to 48 days	To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax and azacitidine for patients with CD33 positive AML

Secondary Outcome Measures

Name	Time	Method
Phase I and II: Lab abnormalities (other than hematologic indices)	Through study completion, up to 2 years	Summary of rate of Grade 3/4 lab abnormalities
Phase I: Overall Response	Up to 6 months	Number of patients who's overall response is CR or CRh or CRi or MLFS
Phase I and II: MRD status	From date of first dose until the date of first documented response, first assessment at 6 months	Number of patients who are MRD negative
Phase I: OS	Phase I: End of 6 months, 12 months, 24 months.	Number of patients who died
Phase I and II: DFS	Through study completion, up to 2 years	Disease-free survival
Phase I and II: Evaluate incidence of AEs and SAEs	Through study completion, up to 2 years	Rate of AEs and SAEs, including infusion-related reactions
Phase I and II: Evaluate BH3 priming assay results	Completion of Cycle 1, estimated 1 month	Summary of assay results
Phase II: OS	Phase II: End of 6 months, 12 months, 24 months	Number of patients who died