A Phase 1 trial evaluating Actimab-A (Lintuzumab-Ac225; Actinium Pharmaceuticals) with salvage chemotherapy regimen CLAG-M in fit patients with relapsed or refractory acute myeloid leukemia (AML), being conducted at the Medical College of Wisconsin as investigator sponsored study, showed positive results.

Acute Myeloid Leukemia or AML is a complex hematological disease often occurring in older patients. In the US, about 19,520 new cases AML occur annually and approximately 10,670 diagnosed patients will die from the disease.

Targeted Radiopharmaceuticals
Actimab-A is a targeted CD33 directed antibody-radiotherapy conjugate (ARC), a highly potent and selective form of targeted radiotherapy. Similar to antibody-drug conjugates (ADCs), ARCs, which include an antibody, linker and radioisotope, are designed to for precision targeting.  And while ADCs deliver a highly potent cytotoxic agent to the tumor cell, ARCs deliver radiation to the tumor cells.

Actimab-A links the radioisotope AC225 to the highly selective targeted, humanized, anti-CD33 antibody lintuzumab. The agent seeks out and bind cancer antigens found on the tumor cell surface, and emit high-energy alpha particles at a limited range, capable of producing double strand DNA breaks, directly to the cancer cell. Because there is no known resistance or repair mechanism for double strand DNA breaks, this approach results in cell death.

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Phase I Study
The development of novel salvage regimens in AML remains an area of great unmet medical need because most AML patients still develop refractory or relapsed disease. Multiple studies have shown that the addition of CD33 directed ARCs to multi-agent chemotherapy may improve remission rates and depth (Minimal Residual Disease/MRD negativity).

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Based on preliminary data, researchers believed that adding Actimab-A to salvage chemotherapy (CLAG-M) for the treatment of patients with AML, would improve remission rates and remission depth in patients with relapsed/refractory Acute myeloid leukemia.

The result of the phase I study, detailed in an abstract which is accepted for an oral presentation at the 64th Annual American Society of Hematology (ASH) Meeting & Symposium being held December 10-13, 2022 in New Orleans, Louisiana, confirm this hypothesis.

The data showed:

  • From all participating patients, 53% reach 1-year Overall Survival (OS) and 32% reached 2-year OS are approximately double outcomes with current approaches
  • Participating patients received a median of 2 lines of prior therapy with 57% receiving prior treatment with venetoclax (Venclexta® and Venclyxto®; AbbVie/Genentech) and 67% had adverse cytogenetics with 52% of patients having a TP53 mutation
Survival, Response and MRD Negativity Findings
The results of the study further showed a
  • Median Overall Survival (OS) of 12 months amongst all patients (n=21)
  • 1-year OS of 53% and 2-year OS of 32%
  • Overall Response Rate (ORR) of 67% across all dose cohorts
  • 72% MRD negativity rate in patients achieving CRc
  • ORR of 83% at the recommended Phase 2 dose of 0.75uCi/kg of Actimab-A with CLAG-M
  • Actimab-A CLAG-M combo was active in patients with TP53 mutations with an ORR of 73% and an ORR of 55% in patients previously treated with venetoclax
Sameem Abedin, MD, Assistant Professor at Froedtert & Medical College Wisconsin and Principal Investigator of the Study.

Difficult to treat
“The median overall survival of 12 months amongst ask patients (n=21) 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 therapy,” said Sameem Abedin, MD, Assistant Professor at Froedtert & Medical College Wisconsin and Principal Investigator of the Study.

“These are extremely difficult to treat patients with very limited treatment options and their expected median overall survival is approximately 2 to 3 months.”

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

Patient Characteristics
Patients participating in this trial had
  • Relapsed or refractory AML and deemed fit with adequate organ function
  • Received a median of two lines of prior therapy (with 57% receiving prior venetoclax therapy.
  • A median age was 63 years

Furthermore,

  • 67% of patients had adverse cytogenetics, 52% had TP53 mutations
  • Patients had median blast CD33 expression of 77% (>25% required for enrollment)
  • 52% of patients had secondary AML or treatment related AML

Overall Survival
“Improvements in overall survival have been difficult to achieve in relapsed or refractory AML patients, particularly for those with TP53 mutations. Additionally, as venetoclax-based treatments have become a standard of care, physicians need better treatment options to then manage the significant number of patients that do not respond, stop treatment due to toxicities or relapse and who have a median overall survival of just 2.4 months,” noted Avinash Desai, MD, Actinium’s Chief Medical Officer.

“We are incredibly excited by these data that clearly show Actimab-A’s potential to improve patient outcomes when combined with CLAG-M. Further, it shows how Actimab-A can be utilized in combination with other therapies and add potency, which supports our strategy to establish it as a backbone therapy for AML with other therapies. With our recommended phase 2 dose finalized and these strong rates of MRD negativity and overall survival, we look forward to providing updates on our development and regulatory strategy as we work to bring this important combination to patients,” Desai concluded.

Presentation Details
TitleLintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features
Abstract Number65
Session Name616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Relapsed/Refractory AML
DateSaturday, December 10, 2022
Time10:30 AM CT
LocationErnest M. Morial Convention Center, Room 220-222

 

Clinical trials
Lintuzumab-Ac225 in Combination With Cladribine + Cytarabine + Filgastrim + Mitoxantrone (CLAG-M) for Relapsed/Refractory Acute Myeloid Leukemia  – NCT03441048

Highlights of prescribing information
Venetoclax (Venclexta® and Venclyxto®; AbbVie/Genentech) [Prescribing Information]

References
[1] Maiti A, Rausch CR, Cortes JE, Pemmaraju N, Daver NG, Ravandi F, Garcia-Manero G, Borthakur G, Naqvi K, Ohanian M, Short NJ, Alvarado Y, Kadia TM, Takahashi K, Yilmaz M, Jain N, Kornblau S, Montalban Bravo G, Sasaki K, Andreeff M, Bose P, Ferrajoli A, Issa GC, Jabbour EJ, Masarova L, Thompson PA, Wang S, Konoplev S, Pierce SA, Ning J, Qiao W, Welch JS, Kantarjian HM, DiNardo CD, Konopleva MY. Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica. 2021 Mar 1;106(3):894-898. doi: 10.3324/haematol.2020.252569. PMID: 32499238; PMCID: PMC7927994.
[2] Ganzel C, Sun Z, Cripe LD, Fernandez HF, Douer D, Rowe JM, Paietta EM, Ketterling R, O’Connell MJ, Wiernik PH, Bennett JM, Litzow MR, Luger SM, Lazarus HM, Tallman MS. Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience. Am J Hematol. 2018 Aug;93(8):1074-1081. doi: 10.1002/ajh.25162. PMID: 29905379; PMCID: PMC6699929.

Featured image: National Cancer Institute on Unsplash, Used with permission

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