Venetoclax and Lintuzumab-Ac225 in AML Patients

• ClinicalTrials.gov Identifier: NCT03867682
• Recruitment Status: Recruiting
• First Posted: March 8, 2019
• Last Update Posted: March 8, 2022
• Sponsor: Actinium Pharmaceuticals
• Information provided by (Responsible Party): Actinium Pharmaceuticals

Study Description

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)

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia; Relapsed Adult AML	Biological: Lintuzumab-Ac225; Drug: Venetoclax; Drug: Spironolactone	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Venetoclax and Lintuzumab-Ac225 in Patients With Refractory or Relapsed AML
• Actual Study Start Date: January 15, 2020
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: January 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Phase I and Phase II; Lintuzumab-Ac225 administered on Day 5 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 taken on Days 1-21 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; 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.; Other Name: Actimab; 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.; Other Name: Venclexta; Drug: Spironolactone; 25 mg by mouth daily, administered on Cycle 1 Day 15 and continued for 12 months after the subject's last treatment with lintuzumab-Ac225.; Other Name: Aldactone

Outcome Measures

Primary Outcome Measures :

1. Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225 [ Time Frame: Cycle 1, up to 48 days ]
   To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 added to venetoclax for patients with CD33 positive relapse/refractory AML.
2. Phase II: Overall Response (CR + CRh + CRi) [ Time Frame: Up to 6 months ]
   To assess the percentage of patients with CR, CRh, CRi or Overall Response (CR + CRh + CRi), up to 6 months after the start of treatment without receiving other AML therapies.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Contacts

Contact: Actinium Pharmaceuticals, Inc.; +1-646-677-3878; actimab@actiniumpharma.com

Locations

United States, California

University of California; Recruiting

Los Angeles, California, United States, 90095

United States, Kentucky

University of Louisville; Recruiting

Louisville, Kentucky, United States, 40202

United States, Louisiana

Ochsner Clinic Foundation; Recruiting

New Orleans, Louisiana, United States, 70121

United States, New York

Weill Cornell Medicine; Recruiting

New York, New York, United States, 10021

United States, Washington

Fred Hutchinson Cancer Research Center; Recruiting

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Actinium Pharmaceuticals

Investigators

• Study Chair: Avinash Desai, MD; Actinium Pharmaceuticals, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Actinium Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03867682
• Other Study ID Numbers: LIN-AC225-AML02
• First Posted: March 8, 2019
• Last Update Posted: March 8, 2022
• Last Verified: February 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Actinium Pharmaceuticals:

Lintuzumab-Ac225; Venetoclax; Lintuzumab; Refractory AML

Additional relevant MeSH terms:

Venetoclax; Lintuzumab; Spironolactone; Antineoplastic Agents; Mineralocorticoid Receptor Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Diuretics, Potassium Sparing; Diuretics; Natriuretic Agents; Antineoplastic Agents, Immunological