Clinical trial NCT03932318: Venetoclax, Azacitidine, and Lintuzumab-Ac225 in AML Patients
Official title: A Phase I/II Study of Venetoclax and Azacitidine and Lintuzumab-Ac225 in Patients With Refractory or Relapsed AML
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Relapsed Adult AML
Keywords: Lintuzumab-Ac225
Venetoclax
Azacitidine
Lintuzumab
Refractory AML
Lead sponsor: Actinium Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2019-04-30
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225
timeFrame: Cycle 1, up to 48 days
measure: Phase II: Overall Response (CR + CRh + CRi + MLFS)
timeFrame: Up to 6 months
Secondary outcomes:
measure: Phase I: Overall Response
timeFrame: Up to 6 months
measure: Phase I: OS
timeFrame: Phase I: End of 6 months, 12 months, 24 months.
measure: Phase II: OS
timeFrame: Phase II: End of 6 months, 12 months, 24 months
measure: Phase I and II: DFS
timeFrame: Through study completion, up to 2 years
measure: Phase I and II: Evaluate incidence of AEs and SAEs
timeFrame: Through study completion, up to 2 years
measure: Phase I and II: Lab abnormalities (other than hematologic indices)
timeFrame: Through study completion, up to 2 years
measure: Phase I and II: Evaluate BH3 priming assay results
timeFrame: Completion of Cycle 1, estimated 1 month
measure: Phase I and II: MRD status
timeFrame: From date of first dose until the date of first documented response, first assessment at 6 months
Other outcomes:
Locations:
Study officials:
affiliation: Actinium Pharmaceuticals, Inc.
name: Avinash Desai, MD
role: STUDY_CHAIR
References: