Clinical trial NCT03867682: Venetoclax and Lintuzumab-Ac225 in AML Patients
Official title: A Phase I/II Study of Venetoclax and Lintuzumab-Ac225 in Patients With Refractory or Relapsed AML
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Relapsed Adult AML
Keywords: Lintuzumab-Ac225
Venetoclax
Lintuzumab
Refractory AML
Lead sponsor: Actinium Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2019-03-08
Enrollment: 38
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 added to venetoclax for patients with CD33 positive relapsed/refractory AML. (Phase 1 portion)
2. 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. 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
3. ECOG ≤ 2
4. Estimated creatinine clearance ≥ 50 mL/min
5. AST and ALT ≤ 3.0 x ULN
6. Bilirubin ≤ 3.0 x ULN

Exclusion Criteria:

1. Active CNS Leukemia.
2. Known HIV infection or known hepatitis B or hepatitis C infection (with a detectable viral load).
3. Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
4. 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.
5. Have received prior radiation to maximally tolerated levels to any critical normal organ.
6. Clinically significant cardiac disease.
7. Active, uncontrolled serious infection.
8. Have other non-myeloid malignancy within 2 years of entry (with exceptions).
9. Psychiatric disorder that would preclude study participation
10. Previous solid organ transplant (prior treatment with SCT is allowed but not if patient has 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)
timeFrame: Up to 6 months
Secondary outcomes:
measure: Phase I: Overall Response
timeFrame: Up to 6 months
measure: Phase I and II: OS
timeFrame: End of 6 months, 12 months, 2 years
measure: Phase I and II: DFS
timeFrame: End of 6 months, 12 months, 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: 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
measure: Phase I and II: Lab abnormalities (other than hematologic indices)
timeFrame: Through study completion, up to 2 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California
state: California
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Actinium Pharmaceuticals, Inc.
name: Avinash Desai, MD
role: STUDY_CHAIR
References:
citation: Garg R, Allen KJH, Dawicki W, Geoghegan EM, Ludwig DL, Dadachova E. 225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. Cancer Med. 2021 Feb;10(3):1128-1140. doi: 10.1002/cam4.3665. Epub 2020 Dec 21.