Venetoclax, Azacitidine, and Lintuzumab-Ac225 in AML Patients

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03932318
• Other study ID #: LIN-AC225-AML03
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• Start date: March 2023
• Est. completion date: September 2024

Study information

• Verified date: July 2023
• Source: Actinium Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: September 2024
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Relapsed Adult AML

Intervention

Biological:
• Lintuzumab-Ac225
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.

Drug:
• Venetoclax
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.
• Azacitidine
75 mg/m2 will be administered on days 1-7 of a 28-day cycle.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Actinium Pharmaceuticals

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Phase I: Overall Response	Number of patients who's overall response is CR or CRh or CRi or MLFS	Up to 6 months
Secondary	Phase I: OS	Number of patients who died	Phase I: End of 6 months, 12 months, 24 months.
Secondary	Phase II: OS	Number of patients who died	Phase II: End of 6 months, 12 months, 24 months
Secondary	Phase I and II: DFS	Disease-free survival	Through study completion, up to 2 years
Secondary	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
Secondary	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
Secondary	Phase I and II: Evaluate BH3 priming assay results	Summary of assay results	Completion of Cycle 1, estimated 1 month
Secondary	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