Actimab-A (lintuzumab-Ac225)

P1, N=26, Active, not recruiting, Medical College of Wisconsin

P1, N=26, Active, not recruiting, Medical College of Wisconsin | Trial primary completion date: Oct 2024 --> May 2024

The combination of lintuzumab-Ac225 and venetoclax had a manageable safety profile and no early mortality at day 30. The MTD was not reached and no significant toxicities have been reported during the follow-up period. Modified dosing schedule in Cohort 4 of the combination demonstrated improved anti-leukemic effects.

We have demonstrated promising therapeutic responses with Actimab-A (lintuzumab- Ac225, an anti-CD33 antibody conjugated with actinium-225) in patients with AML, including in combination trials with chemotherapy regimen CLAG-M and targeted therapy venetoclax...Objective: In this study, we evaluated the antileukemic activity of lintuzumab-Ac225 in FLT3 mutant AML as a single agent and in combination with the FLT3- targeted inhibitor gilteritinib... Our findings show that single-agent lintuzumab-Ac225 has potent antileukemic activity against FLT3 mutant AML and can significantly improve the effect of FLT3 inhibitors in combination. Based on these results, lintuzumab-Ac225 may potentially provide new combination therapy for patients with FLT3 mutant AML.

Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. CLAG-M followed by Lintuzumab-Ac225 yielded significantly better clinical outcomes in high-risk populations, particularly in patients previously treated with venetoclax combinations. The results further support the late-stage clinical development of Lintuzumab-Ac225 in combination with CLAG-M in R/R AML.

P1/2, N=38, Recruiting, Actinium Pharmaceuticals | Trial completion date: Jan 2023 --> Jun 2024 | Trial primary completion date: Dec 2022 --> Nov 2023

P1/2, N=0, Withdrawn, Actinium Pharmaceuticals | N=38 --> 0 | Not yet recruiting --> Withdrawn

In this study, we demonstrate CD33 ARC alpha targeted radiotherapy depletes human CD33 positive immune suppressing MDSCs present in multiple cancer types, to enhance antitumor immunity. These findings present a translatable strategy that supports further evaluation of 225Ac lintuzumab as a MDSC targeting agent to improve the efficacy of antitumor therapies.

Combining lintuzumab-Ac225 up to 1.5 µCi/kg with venetoclax in patients with R/R AML has an acceptable clinical safety profile with no mortality at day 30. The MTD, efficacious dose and dosing schedule of lintuzumab-Ac225 in combination with venetoclax is currently investigated in ongoing Phase I Cohort Expansion.

Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Actimab-A at 0.75uCi/kg, combined with CLAG-M is feasible and safe, and this combination demonstrates a high response rate and MRD negativity in a high-risk AML population. Pharmacokinetics at the RP2D indicate rapid drug clearance. Furthermore, responses appear durable, particularly among patients who are able to proceed to alloHCT.

An I-labeled CD45 antibody (Iomab-B [apamistamab-I131]) is currently studied in the registration-type phase 3 SIERRA trial (NCT02665065) for this purpose...Clinical efforts with At-labeled CD45 antibodies and Ac-labeled CD33 antibodies (e.g. Ac-lintuzumab [Actimab-A]) are ongoing. A first anti-AML RIT may soon become available. This might propel further work to develop RIT-based treatments for AML, with many such efforts already ongoing.

P1/2, N=40, Completed, Actinium Pharmaceuticals | Active, not recruiting --> Completed | N=72 --> 40

P1, N=2, Terminated, Actinium Pharmaceuticals | N=12 --> 2 | Active, not recruiting --> Terminated; Poor recruitment

P1/2, N=38, Recruiting, Actinium Pharmaceuticals | Trial primary completion date: Jan 2021 --> Dec 2022

P1/2, N=38, Not yet recruiting, Actinium Pharmaceuticals | Trial primary completion date: Sep 2022 --> Dec 2023

Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Lintuzumab-Ac225 at a low dose appears to be safe in combination with the salvage chemotherapy regimen CLAG-M. Furthermore, this combination has demonstrated promising efficacy results among high risk RR-AML patients, namely patients with adverse molecular/cytogenetic features and patients previously receiving venetoclax. Updated Cohort 4 results will be presented at ASH.

Combining lintuzumab-Ac225 with venetoclax in patients with R/R AML has an acceptable clinical safety profile with 0% 30-day mortality rate. 67% ORR is particularly encouraging in TP53 -mutant R/R AML. These data support the further evaluation of lintuzumab-Ac225 in combination with venetoclax in patients with R/R AML, especially in TP53 -mutant R/R patients.

There results suggest that the combination of Ac-lintuzumab with venetoclax is a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML. Clinical trial of this combination therapy (NCT03867682) is currently ongoing.

P1/2, N=72, Active, not recruiting, Actinium Pharmaceuticals | Trial completion date: Dec 2020 --> Mar 2021 | Trial primary completion date: Jun 2020 --> Dec 2020