On December 9, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium")reported that highlighted new data from a Phase 1 trial studying Actimab-A in combination with the salvage chemotherapy regimen CLAG-M that was presented in a poster presentation at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Actinium Pharmaceuticals, DEC 9, 2019, View Source [SID1234552095]). The poster reported results from the ongoing Phase 1 combination trial that is being conducted at the Medical College of Wisconsin (MCW). Patients receiving Actimab-A at a dose of 0.50 uCi/kg in the second dose cohort in addition to CLAG-M had an 86% overall response rate (ORR), which is a 56% higher response rate and is substantially greater than what has been observed with CLAG-M and MEC and more than double that of CLAG in a similar patient population that was treated at MCW. Notably, 71% of patients (5/7) achieved negative minimal residual disease (MRD) status in the second dose cohort. In addition to response rates, the poster reported that three patients on the study proceeded to a bone marrow transplant after receiving Actimab-A and CLAG-M. The addition of Actimab-A to CLAG-M appears to have a clinically acceptable safety profile with no patient deaths reported. A table below compares the ORR of patients receiving Actimab-A and CLAG-M to that of the CLAG-M, MEC and CLAG salvage regimens. The full poster can be accessed HERE.

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(PRNewsfoto/Actinium Pharmaceuticals, Inc.)

Regimen

Overall Response Rate

Actimab-A + CLAG-M

86% (6/7)

CLAG-M

55% (41/74)

MEC

44% (25/57)

CLAG

40% (6/15)

Sameem Abedin, M.D., Assistant Professor of Medicine at the Medical College of Wisconsin and Principal Investigator of the study, stated, "CLAG-M has become our preferred salvage regimen for patients with relapsed or refractory AML, as it demonstrated a higher overall response rate than other salvage regimens such as CLAG and MEC. We are pleased by the significantly higher response rate of eighty-six percent that was observed when adding Actimab-A to CLAG-M compared to the fifty-five percent response rate we observed with CLAG-M in prior studies. This efficacy is highly encouraging particularly as the combination appears to have a clinically acceptable safety profile. We look forward to completing this Phase 1 trial and hope to advance to a Phase 2 trial that we believe can serve as a pivotal trial for this promising combination given the high unmet need of patients with relapsed or refractory AML."

Actimab-A is an Antibody Radiation-Conjugate (ARC) that delivers the potent alpha-emitting radioisotope Actinium-225 (Ac-225) via the antibody lintuzumab to cells that express CD33. CD33 is an antigen that is expressed on the vast majority of cancer cells in patients with acute myeloid leukemia (AML). CLAG-M is a salvage chemotherapy comprised of cytarabine, cladribine, G-CSF (granulocyte-colony stimulating factor) and mitoxantrone. The Phase 1 Actimab-A CLAG-M combination study is enrolling patients age 18 and older who have relapsed or refractory AML and are medically fit. The median age of patients enrolled in the trial to date is 62 and all patients had either intermediate risk or poor risk cytogenetics. Three patients had received three or more prior therapies and three patients had received a prior allogeneic bone marrow transplant. This patient population is similar to the study conducted at MCW that enrolled 146 patients, of which, 74 received CLAG-M, 57 received MEC and 15 received CLAG. MRD status was not reported in that study, however 71% of patients receiving 0.50 uCi/kg of Actimab-A and CLAG-M achieved MRD negative status1.

"These results further our excitement for the combination of Actimab-A and CLAG-M as well as other ARC combinations that we have ongoing like that with the Bcl-2 inhibitor venetoclax," commented Dr. Mark Berger, Actinium’s Chief Medical Officer. "The emergence of several recently approved agents, including targeted therapies, for patients with AML is exciting but their use can be limited to patients with a specific mutation and the lack of curative outcomes with these therapies points to a need for continued innovation. Our targeted Antibody Radiation-Conjugates can be a solution to the unmet need of many patients as radiation is a validated modality, hematologic cancers are sensitive and susceptible to radiation and patients with hematologic cancers are typically not exposed to external radiation given the diffuse nature of their disease. Because radiation is agnostic to genetic and cytogenetic abnormalities and there is no known resistance mechanism to alpha particles like actinium-225, we see great potential for additional combinations with other chemotherapy regimens like 7+3, targeted agents like FLT3 and IDH inhibitors and immunotherapies. Finally, these results increase our excitement for the Actimab-A venetoclax combination trial, and our Company looks forward to the clinical results next year that we believe can confirm the synergy we observed in our preclinical research."

The overall response rates observed with the Actimab-A CLAG-M combination compare favorably to response rates reported with recently approved therapies in patients with relapsed or refractory AML that are shown in the table below.

Agent or Regimen

Response Rate

Actimab-A + CLAG-M

83%

Gilteritinib (FLT3 inhibitor)2

68%

Venetoclax + HMA3

64%

Enasidenib (IDH2 inhibitor)4

40%

Venetoclax5

19%

Azacytidine (HMA)6

17%

The Actimab-A CLAG-M Phase 1 trial is expected to be completed in mid-2020. Actinium is also conducting a Phase 1 clinical trial studying Actimab-A in combination with the Bcl-2 inhibitor venetoclax in patients with relapsed or refractory AML to evaluate the safety of the combination and determine if the addition of Actimab-A to venetoclax can increase patient responses and outcomes. In preclinical studies, it was observed that Actimab-A can deplete Mcl-1, a protein that has been implicated in mediating resistance to Bcl-2 inhibitors like Venetoclax and provides a potentiating effect.

Sources:

1) MRD data from a subsequent analysis

2) Perl et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-1740.

3) Aldoss et al. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica. 2018 Sep;103(9):e404-e407.

4) Stein et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10;130(6):722-731.

5) Konopleva et al. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016 Oct;6(10):1106-1117.

6) Itzykson et al. Azacitidine for the treatment of relapsed and refractory AML in older patients. Leuk Res. 2015 Feb;39(2):124-30.