Actinium Pharmaceuticals announced the first patient has begun treatment in the third and final cohort of the Actimab-A CLAG-M combination trial. This Phase 1 trial is an investigator-initiated trial being conducted at the Medical College of Wisconsin in patients with relapsed or refractory acute myeloid leukemia (AML). Patients in the third cohort will receive a cycle of CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) followed by 0.75 uCi/kg of Actimab-A on day 6, 7 or 8. Actimab-A is an antibody radiation conjugate (ARC) that targets the CD33 receptor on blood cancer cells and delivers potent cytotoxic radiation via the radioisotope Actinium-225. This trial will enroll up to 18 patients and will evaluate the safety of this combination including determining the maximum-tolerated dose as well as response rates, progression-free survival and overall survival. Actinium expects the third cohort to be completed mid-2020.
Patients in the trial to date have been high-risk with intermediate and poor risk cytogenetics with most patients having received three or more prior therapies including bone marrow transplant in some patients. Patients in the first cohort received 0.25 uCi/kg of Actimab-A and the second cohort received 0.50 uCi/kg of Actimab-A. In a prior Phase 1/2 trial of Actimab-A single agent in newly diagnosed AML with 58 patients the 0.5 uCi/kg dose was sub-therapeutic (with response rates of 17%, 22% and 69% at doses of 1.0, 1.5 and 2.0 uCi/kg respectively). In this trial, the second cohort with CLAG-M plus the sub-therapeutic 0.5 uCi/kg dose showed that 86% (6/7) of patients achieved complete remission (CR/CRi) after receiving the 0.50 uCi/kg dose. This is a nearly 60% increase over the remission rate reported in a trial of seventy-four patients with relapsed or refractory AML who received CLAG-M alone. Further, 71% (5/7) of patients achieved negative minimal residual disease (MRD) status following treatment with the combination. MRD negative status means the patient had no detectable disease after treatment. Assuming a successful outcome of the Phase 1 trial, Actinium intends to advance this combination to a Phase 2 randomized trial to demonstrate significance.
"These rates of high complete remission and MRD negative status are not easily achieved in AML let alone in patients with high-risk relapsed or refractory disease. However, AML, and other hematologic cancers, are highly radiation sensitive. Targeting the CD33 receptor on AML cells with potent alpha radiation via an Actinium-225 ARC hits these cells with a cytotoxic agent they have not been exposed to before and have no resistance mechanism against. The result is significant DNA damage that can have a profound anti-tumor effect via targeted delivery that overcomes the limitations of current radiation delivery methods," said Dr. Mark Berger, Actinium's Chief Medical Officer. "It is exciting to see data supporting our hypothesis that improved outcomes can be achieved with an ARC therapy in combination with chemotherapy. We feel these results support the additive benefits, mechanistic synergy and potentiating abilities of ARC combinations. We have great excitement for the third and final cohort and hope to improve on the already encouraging results we have seen thus far."
Remission rates achieved with Actimab-A in combination with CLAG-M in this Phase 1 trial compare favorably to targeted agents recently approved for patients with relapsed or refractory AML.
