Actimab-A Triplet Trial Launches in Frontline AML
A phase 1 trial is evaluating Actimab-A, venetoclax, and ASTX-727 in frontline acute myeloid leukemia, with initial data expected later this year.
Acute myeloid leukemia (AML) cells: © LASZLO - stock.adobe.com
The first clinical trial under the Cooperative Research and Development Agreement with the National Cancer Institute and Actinium Pharmaceuticals, Inc, for Actimab-A has been initiated (NCT06802523) and plans to evaluate the triplet combination of Actimab-A, venetoclax (Venclexta), and ASTX-727 in the frontline for patients with acute myeloid leukemia (AML).1
Actimab-A is a humanized anti-CD33 antibody conjugated to Actinium-225 (Ac-225). With its potent alpha-particle payload Ac-225, the agent causes lethal double strand DNA breaks for which there are no known resistance or repair mechanisms.
The combination of actimab-A and venetoclax previously was tested in a multicenter, phase 1 trial where it was well tolerated and led to manageable adverse events in patients with AML. Preclinically, Actimab-A also demonstrated its synergistic effects when given with venetoclax by depleting MCL-1.
"We are incredibly excited that the first Actimab-A trial initiated under our CRADA with the NCI is this triplet combination with venetoclax and Taiho's ASTX-727. While Ven-HMA has positively impacted outcomes in AML, a significant number of patients have poor responses or relapse quickly resulting in dismal outcomes,” said Avinash Desai, MD, Actinium's chief medical officer, in a press release. “We believe Actimab-A's potentially synergistic, and mutation agnostic mechanism of action can improve clinical outcomes for these patients by producing deeper remissions, including measurable residual disease negativity, that are more durable.”
About the Phase 1 Study of Actimab-A
In the phase 1, randomized trial, investigators plan to assess the rate and duration of complete remission (CR) and safety, including the optimal dose, of the combination of Actimab-A, venetoclax, and ASTX-727, in patients with a confirmed diagnosis of AML per the 2022 WHO criteria and be deemed unsuitable for intensive chemotherapy due to frailty or comorbidities.1 This study represents the first ever triplet combination with targeted radiotherapy used as a backbone in AML.
Eligible patients must be aged 18 years or older, have an ECOG performance status of 0 to 3, and demonstrate adequate organ function.2 Prior chemotherapy for antecedent myelodysplastic syndrome or myeloproliferative neoplasms is excluded.
For HIV, HBV, or HCV-infected patients, viral loads must be undetectable on appropriate therapy. Patients with prior or concurrent malignancies are eligible if they do not interfere with the study regimen. Cardiac function must be assessed, with heart failure limited to NYHA class II or below. Hydroxyurea, cytarabine, or leukopheresis is permitted for hyperleukocytosis, and white blood cells must be < 25 x 109/L before starting therapy.
This study involves a dose-escalation phase followed by a dose-expansion phase of the combination. Patients are randomized to 1 of 2 schedules during dose-escalation, and if both schedules are used in dose-expansion, randomization continues.
Schedule 1 consists of:
Induction: Patients will receive Actimab-A via intravenous (IV) infusion on day 8, venetoclax orally and daily on days 1 to 28, and ASTX-727 orally and daily on days 1 to 5 of cycle 1.
Re-induction: Patients with CR, partial response (PR), or no response (NR) after cycle 1 receive the same regimen in cycle 2.
Maintenance/Consolidation: Patients with CR with incomplete hematologic recovery (CRi), CR with partial hematologic recovery (CRh), or morphologic leukemia-free state (MLFS) after cycle 1 receive venetoclax orally and daily on days 1 to 28 and oral ASTX-727 daily on days 1 to 5 of each 28-day cycle until disease progression or unacceptable toxicity.
Schedule 2 includes:
Induction: Patients receive Actimab-A IV on day 1, oral venetoclax daily on days 1 to 28, and oral ASTX-727 daily on days 1 to 5 of cycle 1.
Re-induction: Patients with CR, PR, or NR after cycle 1 receive the same regimen in cycle 2.
Maintenance/Consolidation: Patients with CRi, CRh, or MLFS after cycle 1 receive orally venetoclax daily on days 1 to 28 and ASTX-727 orally and daily on days 1 to 5 of each 28-day cycle until disease progression or unacceptable toxicity.
All patients undergo bone marrow aspiration/biopsy and blood sample collection throughout the study. After treatment, patients are followed every 3 months for up to 3 years.
The primary end point of the study is to determine the recommended phase 2 dose of the combination. Secondary end points consist of determining the combinations maximum tolerated dose, rate and time to CR, CRi, and CR with partial hematologic recovery, duration of remission, progression-free survival, event-free survival, overall survival, clinical activity, and toxicities.
The study plans to enroll approximately 48 patients and has an estimated study completion date of September 2025. Initial data from the trial are expected to be released in the second half of 2025.
“Due to its mutation agnostic mechanism, Actimab-A can overcome high-risk features, such as TP53 mutations, and has demonstrated the ability to improve outcomes in these patients where Ven-HMA has had limited success. This triplet regimen can be conveniently administered in the outpatient setting as venetoclax and ASTX-727 are both oral agents and Actimab-A does not require isolation given that it is an alpha-particle emitter. We are eager to collaborate with NCI on this important study to evaluate earlier intervention with a CD33 targeted radiotherapy in patients with AML," concluded Desai, in the press release.1
REFERENCES:
Actinium Pharmaceuticals Announces Initiation of Actimab-A Triplet Combination Frontline Trial Under NCI CRADA with Venetoclax and Taiho Oncology's Hypomethylating Agent ASTX-727 in Patients with Newly Diagnosed AML. News release. Actinium Pharmaceuticals, Inc. March 11, 2025. Accessed March 12, 2025. https://tinyurl.com/359chrye
Testing the combination of targeted radiotherapy with anti-cancer drugs, venetoclax and ASTX-727, to improve outcomes for adults with newly diagnosed acute myeloid leukemia. ClinicalTrials.gov. Updated February 7, 2025. Accessed March 12, 2025. https://clinicaltrials.gov/study/NCT06802523?intr=Actimab-A&rank=6
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