Date: 2016-06-03
Type of information: Results
phase: 1-2
Announcement: results
Company: Actinium Pharmaceuticals (USA - NJ)
Product: Actimab-A - Lintuzumab-Ac225
Action
mechanism: monoclonal antibody/radioimmunotherapy. Actimab-A is a radiolabeled antibody being developed for newly diagnosed AML in patients over 60, and is currently in a multicenter Phase 1/2 clinical trial. Actimab-A consists of the monoclonal antibody, HuM195, and the radioisotope, actinium-225. Actinium-225 decays by giving off high-energy alpha particles, which kill cancer cells. When actinium decays, it produces a series of daughter atoms, each of which gives off its own alpha particle, increasing the chances that the cancer cell will be destroyed. HuM195 is the humanized version of M195 and is a monoclonal antibody that targets CD33, which is abundantly found on myeloid leukemia cells. Both the alpha particle technology and HuM195 were initially developed at Memorial Sloan Kettering Cancer Center.
Disease: newly diagnosed acute myeloid leukemia (AML) in elderly patients
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The study is a multicenter, open label Phase I/II trial. The goal of the Phase I part of this study is to find the highest tolerable dose of Lintuzumab-Ac225 that can be given with cytarabine to patients with acute myeloid leukemia. The goal of the Phase II part of this study is to learn if Lintuzumab-Ac225 and cytarabine can control acute myeloid leukemia. The safety of this drug combination will also be studied. (NCT02575963)
Latest
news: * On June 3, 2016, Actinium Pharmaceuticals announced positive results from its Phase 1 Actimab-A trial in patients newly diagnosed with acute myeloid leukemia (AML) who are over the age of 60. The median age of patients in the trial was 77 years (range 68-87 years) of which 67% had intermediate-risk cytogenetics and 33% had unfavorable cytogenetics. Importantly, the complete response rate at the dose level which the company intends to progress into the Phase 2 trial was 50% in patients with low peripheral blast (PB) burden. Most serious adverse events (SAEs) were infections and cytopenias that are considered to be consequences of acute myeloid leukemia and not drug related. * On March 18, 2015, Actinium Pharmaceuticals announced the completion of the third cohort of the Company's ongoing multi-center Phase 1/2 Study for Actimab-A for the treatment of newly diagnosed Acute Myeloid Leukemia (AML) in elderly patients. Cohort 3, which included 3 additional patients, demonstrated no dose limiting toxicities in patients older than 60 and up to 87 years of age who were not eligible for currently approved therapies. Two out of three Actimab-A treated patients achieved complete remission with different degrees of hematological recovery (CRi). These responses were documented in the settings of high pre-treatment leukemia burdens of up to 88% in the bone marrow. In the previous cohort treated at a lower dose level of Actimab-A, one patient achieved CRi. "The positive results on both safety and anti-leukemic effect demonstrated in the completed third cohort represents a significant achievement for the Actimab-A program, and supports the advancement to a higher dose with the potential to further enhance the already strong results we have seen to date," stated Dragan Cicic, MD, Chief Medical Officer of Actinium. "We believe the responses observed for Actimab-A, with minimal toxicity being reported, are impressive in this disease setting. These findings build upon those presented and published over the past year which demonstrated a clear survival benefit in secondary AML patients. We remain steadfast in our belief that Actimab-A could play an important role in the treatment regimen for newly diagnosed elderly secondary AML patients who currently have limited treatment options, and have historically achieved overall survival of only 2 to 5 months, depending on treatment modality." The primary goals of the Phase 1 trial portion of the ongoing Phase 1/2 clinical trial are to establish the safety profile, determine the maximum tolerated dose (MTD) and assess the preliminary clinical activity of Actimab-A in newly diagnosed AML patients over 60. In the first cohort, patients were treated with two doses of Actimab-A at 0.5 ?Ci/kg activity level. In the second cohort, patients received two doses of Actimab-A at 1.0 ?Ci/kg activity level, and in the third cohort, patients received two doses at 1.5 ?Ci/kg activity. As the drug candidate continues to be well tolerated in in these high risk elderly AML patients, the trial will advance to a fourth cohort at two doses of Actimab-A at a ?Ci/kg activity level of 2.0. Upon reaching the MTD in the Phase 1 portion of the trial, the Phase 2 portion would begin at the established MTD level. Actinium previously announced positive interim data from the ongoing Phase 1/2 trial of Actimab-A in older patients with newly diagnosed AML. Most notably, median overall survival ("OS") of the seven secondary AML patients (with prior myelodysplastic syndrome, or MDS) in the study was 9.1 months, which compares favorably to historical norms of 2 to 5 months, depending on the treatment modality. Older AML patients are already higher risk, with secondary AML patients considered to have the more severe and less treatable form of AML, and as a consequence, have shorter expected survival. The clinical abstract was published and is available online in Blood, the official Journal of the American Society of Hematology.
The company announced that it will proceed with a Phase 2 trial with Actimab-A at 2 µCi/kg/fractionated dose, the highest dose level from the Phase 1 trial. For the Phase 2 trial, modifications will be made to the protocol including the removal of low dose cytarabine, which has already been agreed to with the FDA, and the mandatory use of hydroxyurea, which can be used per the current protocol, to reduce PB burden with the goal of accelerating patient enrollment and improving patient outcomes.
The recently completed Phase 1 trial totaled 18 patients having a median age of 77 of which 78% were 75 and older and 28% were 80 and older. Complete responses were observed in 28% of patients at all dose levels and in the three highest dose levels complete response rates equaled 33%. Importantly, the complete response rate at the dose level which the Company intends to progress into the Phase 2 trial was 50% in patients with low PB burden. Of the 18 patients, 67% presented with low PB burden. Also, 67% of patients had secondary AML resulting from myelodysplastic syndrome (MDS). No early mortality was observed within 28 days and 56-day early mortality was observed in 11% of patients. Dose limiting toxicities (DLTs) were observed in 2 patients and both were grade 4 and neither of which were extramedullary. Most serious adverse events (SAEs) were infections and cytopenias that are considered to be consequences of AML and not drug related.
The Phase 2 portion of the trial will enroll an additional 47 patients bringing the total number of patients in the Phase 1/2 Actimab-A trial to 65. This multi-center, single arm trial will enroll patients newly diagnosed with AML who are over the age of 60. The number of centers for the Phase 2 portion of the trial are expected to be at least double the number of centers in the Phase 1 portion of the trial. In addition, the protocol for the Phase 2 trial has been revised to eliminate low dose cytarabine, which the FDA has already agreed to. The peripheral blast burden key threshold level will serve as an inclusion criteria going forward and the use of hydroxyurea to control peripheral blast burden, which was permitted in the Phase 1 protocol, will be mandated in order to lower PB burden. Patient enrollment is expected to commence in the second half of 2016
