Phase I/II Actimab-A AML Trial with two consecutive fractionated doses

This is a multicenter corporate trial in newly diagnosed AML patients over the age of 60.  API is working with investigators at 5 centers (MSKCC, Johns Hopkins Medicine, University of Pennsylvania Health System, Fred Hutchinson Cancer Center and MD Anderson Cancer Center) on conducting the trial.   API currently expects that it will take approximately 9 months to complete the Phase I portion of the trial and an additional 1- 1.5 years to complete the Phase II portion of the trial.  In this Phase I/II study, patients are eligible if they have previously untreated newly diagnosed acute myeloid leukemia according to World Health Organization criteria, are age 60 years or older, and are unfit for or decline intensive chemotherapy, or are 70 years or older with newly diagnosed AML.  This target population has historically had better outcomes than relapsed and refractory patients who have been most of the patients in API’s previous AML trials.  

Maximum enrollment in the Phase I portion of the trial is 21 patients in dose escalating cohorts of 3 patients each with the goal of determining the maximum tolerated dose (MTD) for Actimab-A.  There is a six week interval between dose levels.  Once MTD has been determined, it will be used as the dose level for the Phase II portion of the trial which will enroll up to 53 patients.  There are 4 planned dose levels in the Phase I portion of the trial.This multicenter trials builds upon the experience and results of our previous trials with the same antibody labeled with alpha emitters actinium 225 and its daughter isotope bismuth 213 in acute myeloid leukemia patients who failed previous therapies, both standard and experimental, or were deemed particularly high risk and unlikely to respond to other therapies.  These prior clinical trials include the Bismab-A trials referenced above and Actimab-A single dose trials referenced below.

Phase I Trial with single dose of Actimab-A

In collaboration with MSKCC we are conducting a first-in-man Phase I dose escalation trial to determine the safety, pharmacology, and biological activity of Actimab-A in AML.  Eighteen patients (median age, 68 yrs; range, 45–80 yrs) with relapsed/refractory AML were treated to date.  Patients received a single infusion of Actimab-A at doses of 0.5, 1, 2, 3, or 4 µCi/kg (µCi –microCurie; total dose, 23–390 µCi).  No acute toxicities were seen.  Dose limiting toxicity (DLT) was suppression of the entire bone marrow lasting over 35 days and consequent death due to sepsis.  It occurred in one patient treated with 3 µCi/kg and in both patients receiving 4 µCi/kg.  Toxicities outside of the target organ (bone marrow) were limited to transient grade 2/3 liver function abnormalities.  With follow-up from 1–24 months (median, 2 months), no evidence of damage to kidneys due to radiation was seen.  Peripheral blood blasts (leukemia cells) were eliminated in 10 of 16 evaluable patients who received a full treatment dose.  Eight patients had reductions of 50% or more, including 3 patients with 5 percent or fewer blasts.  Actimab-A is tolerable at doses less than 4 µCi/kg and has antileukemic activity.  The trial continues.

Acute Myeloid Leukemia is characterized by very high numbers of immature white blood cells of certain kind that are similar to normal young blood cells and all immature white blood cells are called blasts.  It is not normal for a person to have any blasts in circulating in peripheral blood (peripheral blasts) and to have more than 5 percent of blasts in the bone marrow.  The table below shows how the administration of Actimab-A has changed amounts of blasts in peripheral blood and bone marrow of AML patients at different doses of Ac-225 activity (dose levels).