A groundbreaking clinical trial investigating a novel triplet therapy for frontline acute myeloid leukemia (AML) treatment has been initiated under a Cooperative Research and Development Agreement between Actinium Pharmaceuticals and the National Cancer Institute (NCI).
The phase 1 trial (NCT06802523) will evaluate the combination of Actimab-A, venetoclax (Venclexta), and ASTX-727 in newly diagnosed AML patients who are deemed unsuitable for intensive chemotherapy due to frailty or comorbidities. This marks the first-ever triplet combination using targeted radiotherapy as a backbone in AML treatment.
The Novel Combination Approach
Actimab-A is a humanized anti-CD33 antibody conjugated to Actinium-225 (Ac-225), a potent alpha-particle emitter that targets CD33—a marker expressed ubiquitously on myeloid blasts in patients with AML and other hematologic malignancies. The alpha-particle payload causes lethal double-strand DNA breaks for which there are no known resistance or repair mechanisms.
Venetoclax, an oral Bcl-2 inhibitor, is already approved in combination with hypomethylating agents (HMAs) for patients with newly diagnosed AML. ASTX-727 is a novel oral hypomethylating agent developed by Taiho Pharmaceuticals.
Previous clinical research has shown promising results for Actimab-A when combined with venetoclax. In a multicenter phase 1 trial, the combination was well-tolerated and led to manageable adverse events in AML patients. Preclinical studies demonstrated synergistic effects when Actimab-A was 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," said Avinash Desai, MD, Actinium's chief medical officer. "While Ven-HMA has positively impacted outcomes in AML, a significant number of patients have poor responses or relapse quickly resulting in dismal outcomes."
Trial Design and Patient Population
The phase 1 randomized trial will assess the rate and duration of complete remission and safety, including determining the optimal dose of the combination. Eligible patients must be 18 years or older with a confirmed diagnosis of AML per the 2022 WHO criteria and have an ECOG performance status of 0 to 3 with adequate organ function.
The study involves a dose-escalation phase followed by a dose-expansion phase, with patients randomized to one of two treatment schedules:
Schedule 1:
- Induction: Actimab-A via intravenous infusion on day 8, venetoclax orally daily on days 1-28, and ASTX-727 orally daily on days 1-5 of cycle 1
- Re-induction: Same regimen in cycle 2 for patients with complete response, partial response, or no response after cycle 1
- Maintenance/Consolidation: Venetoclax and ASTX-727 for patients with CR with incomplete hematologic recovery, CR with partial hematologic recovery, or morphologic leukemia-free state
Schedule 2:
- Induction: Actimab-A IV on day 1 (instead of day 8), with the same venetoclax and ASTX-727 schedule as in Schedule 1
- Re-induction and Maintenance/Consolidation: Follow the same pattern as Schedule 1
All patients will undergo bone marrow aspiration/biopsy and blood sample collection throughout the study and will be followed every three months for up to three years after treatment.
Addressing Unmet Needs in AML Treatment
The primary endpoint of the study is to determine the recommended phase 2 dose of the combination. Secondary endpoints include determining the maximum tolerated dose, rate and time to complete remission, duration of remission, progression-free survival, event-free survival, overall survival, clinical activity, and toxicities.
Dr. Desai emphasized the potential of this approach: "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."
Outpatient Administration and Future Outlook
A notable advantage of this regimen is its potential for outpatient administration. Both venetoclax and ASTX-727 are oral agents, and Actimab-A does not require isolation since it is an alpha-particle emitter.
"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," added Dr. Desai.
The study plans to enroll approximately 48 patients with an estimated completion date of September 2025. Initial data from the trial are expected to be released in the second half of 2025.
This innovative approach represents a significant step forward in the treatment landscape for AML, particularly for patients with high-risk features who typically respond poorly to standard therapies.
