Lintuzumab-Ac225 and Intensive Chemotherapy Elicits High Response Rates in AML

A phase 1 trial (NCT03441048) examining lintuzumab-Ac225 (Actimab-A) with salvage chemotherapy regimen CLAG-M (cladribine, cytarabine, G-CSF, mitoxantrone) in patients with relapsed or refractory acute myeloid leukemia (AML) demonstrated positive survival and response rates, according to Actinium Pharmaceuticals, Inc.¹

At 1-year, the overall survival (OS) rate was 53% and 32% at 2 years. These data are approximately double the outcomes which have been observed with current approaches. Further data will be presented at the 64th American Society of Hematology Annual Meeting & Symposium on Saturday, December 10, 2022.

"The median overall survival of 12 months and 2-year overall survival of 32% is highly impressive in these relapsed or refractory patients, where a majority of treated patients have adverse cytogenetics including tp53 mutations and received prior venetoclax [Venclexta] therapy. These are extremely difficult to treat patients with very limited treatment options and their expected median overall survival is approximately 2 to 3 months," stated Sameem Abedin, MD, assistant professor at Froedtert & Medical College Wisconsin and principal investigator of the study, in the press release.

This trial is a prospective, single-center, phase 1 clinical study looking to assess the maximum-tolerated dose (MTD) of lintuzumab-Ac225 combined with CLAG-M chemotherapy for patients with AML. A 3 + 3 study design is utilized in the trial and a 5-patient cohort at the recommended phase 2 dose.²

Patients aged 18 years and older with relapsed or refractory AML who were deemed fit, had an ECOG performance status of 0-2, and adequate organ function, were enrolled in the trial. Further, greater than 25% of blasts must have been CD33 positive on flow cytometry using a Phycoerythrin labeled anti-CD33 antibody, and patients must have been in their first or subsequent relapse or refractory status after prior therapy, with or without prior hematopoietic stem cell transplant. Patients with myelodysplastic syndrome and progression to AML on hypomethylating agents also will be included.

Primary end points of the trial include number of subjects with dose-limiting toxicities, MTD, number of subjects who have at least 1 serious adverse event related to the study, and overall survival. The secondary end points include number of subjects with a complete response (CR), CR with incomplete hematologic recovery, morphologic leukemia-free state, experiencing partial remission, and progression-free survival.

Those enrolled received a median of 2 lines of prior therapy with 57% having received prior treatment with venetoclax. A total of 67% of patients had adverse cytogenetics, and 52% had tp53 mutations.

The median age of patients 63 years. Further, patients had median blast CD33 expression of 77% and 52% of patients enrolled had secondary AML or treatment related AML.

Findings revealed that among all patients (n = 21), the median OS was 12 months with a 1-year OS rate of 53% and 2-year OS rate of 32%. Across all dose cohorts, the ORR was 67%, and there was a 72% minimal residual disease (MRD) negativity rate in patients who achieved a CR.

At the recommended phase 2 dose of 0.75uCi/kg of lintuzumab-Ac225 with CLAG-M, the ORR was 83%. Overall, the combination of lintuzumab-Ac225 and CLAG-M was active in patients with AML harboring tp53 mutations with an ORR of 73% and an ORR of 55% in patients previously treated with venetoclax.

"These data strongly support the further clinical development of this novel targeted radiotherapy-based combination. We are excited that our hypothesis of adding lintuzumab-Ac225 to CLAG-M to eliminate residual leukemia cells, resulting in deeper remissions and survival with acceptable tolerability given targeted nature of lintuzumab-Ac225 is strongly supported by these findings," concluded Abedin, in the press release.

REFERENCES:

1. Actinium announces positive 1-Year and 2-Year overall survival data for patients with relapsed or refractory AML in phase 1 actimab-A CLAG-M combination trial. News release. Actinium Pharmaceuticals, Inc. November 3, 2022. Accessed November 3, 2022. https://prn.to/3TaA2IU

2. Lintuzumab-Ac225 in combination with cladribine + cytarabine + filgrastim + mitoxantrone (CLAG-M) for relapsed/refractory acute myeloid leukemia. ClinicalTrials.gov. Updated October 20, 2022. Accessed November 3, 2022. https://clinicaltrials.gov/ct2/show/NCT03441048?term=CLAG-M&cond=AML&draw=2&rank=4