Actinium reports complete response in the Actimab-A venetoclax combination trial

Actinium Pharmaceuticals has reported 67% overall response rate in first cohort in Actimab-A Venetoclax combination trial in relapsed and refractory AML at ASH, which includes one complete response in patient with TP53 mutation and one partial response reported in patients with poor risk adverse cytogenetics with subtherapeutic dose of Actimab-A indicative of mechanistic synergy with venetoclax.

Next generation sequencing showed elimination of certain mutations after only one cycle of Actimab-A and venetoclax combination with no DLT’s reported, Actinium said.

The findings from the first dose cohort of the Phase 1 portion of the Actimab-A venetoclax Phase 1/2 combination trial in patients with relapsed or refractory Acute Myeloid Leukemia (AML) were presented at the 62^nd American Society of Hematology (ASH) annual meeting.  The poster presentation highlighted results from the first three patients treated with the initial subtherapeutic dose level of 0.5 μCi/kg of Actimab-A and venetoclax, Actinium said.

Actinium said in a press release announcing the results, that the enrolled patients had a median of 2 prior therapies (range 2-3) and a median bone marrow blast percentage of 30% (range 20 – >60).  All 3 patients had poor risk disease with adverse cytogenetics, and each patient had an additional high-risk marker (FLT3-ITD+, antecedent JAK2+ myelofibrosis, or TP53 mutation).  One patient who had multiple genetic mutations including IDH2, RUNX1, TP53 and others, achieved a complete remission with incomplete blood count recovery (CRi) after the first cycle of Actimab-A and venetoclax.  Next generation sequencing at the end of the first cycle showed that patient was negative for the known IDH2 and RUNX1 mutations.  This patient has continued treatment receiving the second cycle and their bone marrow remains normocellular with no excess blasts.  In addition, another patient achieved a partial response after one cycle of Actimab-A and venetoclax.  There were no Actimab-A related dose limiting toxicities or nonhematologic Grade 3 or greater related AEs reported in the first cohort.  The trial has advanced to the second dose cohort of 1.0 μCi/kg of Actimab-A and venetoclax with patient enrollment ongoing.

Sandesh Seth, Actinium’s Chairman and Chief Executive Officer, expressed excitement to highlight the promising data emerging from both of the company’s combination trials with Actimab-A in the R/R AML setting, namely the Actimab-A venetoclax and Actimab-A CLAG-M trials.  Seth said that particularly compelling was the complete response reported in a patient with complex mutations like TP53 with Actimab-A and venetoclax and the high MRD negativity rate with Actimab-A and CLAG-M. The CEO said that the results clearly demonstrate that a superior clinical effect without adding meaningful toxicity is achievable using Ac-225 ARC’s to precisely deliver powerful internal radiation and elicit a potentiating and synergistic treatment effect with chemotherapy and targeted agents.  “With this clinical validation in hand, we look forward to expanding our ARC combinations with other therapeutic modalities in AML and into additional indications to further establish our leadership position in the field by leveraging our enhanced R&D capabilities including new research facilities and key hires,” said Seth.

Dr. Mark Berger, Actinium’s Chief Medical Officer, was also thrilled to have reported a complete response in the Actimab-A venetoclax combination trial, in addition to the partial response previously highlighted in the abstract.  He said that both responses occurred after just one cycle of a subtherapeutic dose of Actimab-A. According to Berger, the initial results, the one complete response and safety profile to date, support the potential mechanistic synergy of Actimab-A with venetoclax.  “As a single agent, venetoclax has produced low response rates of 19% in patients with R/R AML so we are pleased with the results seen in our first dose cohort.  In addition, the clinical data from Actimab-A and Iomab-B presented at this year’s ASH demonstrates our strong commitment to addressing the unmet needs of patients with R/R AML with our ARCs as best in class therapeutics, bridge to transplant and targeted conditioning for potentially curable bone marrow transplant.  With this in mind, we look forward to guidance on Iomab-B expected from the ad-hoc DMC meeting before year-end,” said Berger.

This Phase 1/2 trial is a multicenter, open label trial of Actimab-A (lintuzumab-Ac225) added to venetoclax for patients with CD33 positive R/R AML.  A Phase 2 trial studying Actimab-A as a single agent produced a 69% overall response rate in older unfit patients with newly diagnosed AML.  In a poster presentation at the American Association of Cancer Research (AACR) Annual Meeting 2019, Actimab-A was shown to be synergistic with venetoclax in venetoclax resistant cell lines, by depleting MCL-1, a protein shown to mediate resistance to venetoclax.  Further, the induction of direct AML cell death via double-stranded DNA breaks by Actimab-A provides a second mechanism for enhancing synergistic potency with venetoclax.  Venetoclax is a B-Cell Lymphoma 2 (BCL-2) inhibitor that is jointly developed and marketed by AbbVie and Genentech and is approved for patients with AML, Chronic Lymphocytic Leukemia (CLL), and Small Lymphocytic Leukemia (SLL).  Despite its approval in AML, venetoclax has produced low response rates of 19% as a single agent in R/R AML.¹ This is due in part to the type of AML, risk factors, and cytogenetics of this patient population.  The Phase 2 trial results, together with a synergistic mechanism of action with venetoclax demonstrated in pre-clinical studies, are driving this combination trial with an initial focus on the high unmet needs of R/R patients including those who have relapsed or do not respond to treatment with venetoclax based regimens.