An early trial testing the investigational radioimmunotherapy Actimab-A plus chemotherapy in people with relapsing or refractory acute myeloid leukemia (AML) has begun dosing a final group of patients, Actinium Pharmaceuticals announced.
Preliminary results show patients entering into complete remission with this combination, at rates favorable to other recently approved therapies targeting AML, the company reports. Seventy-one percent of those in a mid-level dosing group became free of any detectable signs of the disease — a status called minimal residual disease (MRD) negativity — on Actimab-A plus chemotherapy.
Actimab-A (lintuzumab-Ac225) is an antibody radiation conjugate (ARC), or radioimmunotherapy, that targets the CD33 receptor present on blood cancer cells. It works as a type of radiation therapy, in which a radioactive substance (radioisotope Actinium-225) is linked to a CD33-targeted antibody (lintuzumab).
The antibody selectively binds to and gives off potent radiation directly to tumor cells, which is expected to help kill them. The agent is delivered through into-the-vein (intravenous) infusions.
The Phase 1 trial (NCT03441048), being conducted at the Medical College of Wisconsin, is evaluating the safety of Actimab-A combined with a chemotherapy regimen. Study goals include determining the maximum tolerated dose, as well as patients’ response rates, survival without disease worsening, and overall survival.
Investigators expect to enroll up to 18 people at its one Milwaukee site; information can be found here.
Patients are being assigned a fixed dose of CLAG-M chemotherapy (cladribine, cytarabine, G-CSF, and mitoxantrone) followed by one of three doses of Actimab-A — 0.25, 0.50, or 0.75 uCi/kg administered as a single dose on day six, seven, or eight of each cycle.
All in the first and second groups (0.25 and 0.50 uCi/kg) have been dosed, and the first patient in the enrolling third group (0.75 uCi/kg) has now been dosed. Actinium expects to finish treating this final trial group by midyear.
In a prior Phase 1/2 trial evaluating Actimab-A alone in 58 newly diagnosed AML patients, the 0.5 uCi/kg dose was found to be sub-therapeutic, considering that patient response rates were 17%, 22% and 69% for a dose of 1.0, 1.5 and 2.0 uCi/kg, respectively.
In the study now underway, 86% of the patients (6 of 7) in the second dosing group were given Actimab-A at that sub-therapeutic 0.5 uCi/kg dose, but in combination with CLAG-M, and went into complete remission. Typically this means that a patient’s bone marrow contains fewer than 5% blast cells (leukemia cells), blood cell counts return to within normal limits, and there are no signs or symptoms of the disease.
Such a remission rate represents a nearly 60% improvement over that reported for relapsed or refractory AML patients treated with CLAG-M chemo alone.
Moreover, 71% of the patients (5 of 7) in this second combo group achieved minimal residual disease (MRD) status — which means that a patient cleared all detectable signs of cancer. That is, no signs of leukemia were evident in the bone marrow, even using sensitive lab tests.
The remission rates verified so far were also superior to those seen for patients given targeted agents recently approved, including Xospata (gilteritinib; 68% remission rate), Venclexta (venetoclax) plus a hypomethylating agent (azacitidine or decitabine; 64% remission rate) and Idhifa (enasidenib; 40% remission rate).
The combination has also had a clinically acceptable safety profile.
Assuming the trial is completed successfully, Actinium plans to advance the combination to a larger, randomized Phase 2 trial to confirm these preliminary results and provide support for Actimab-A’s approval.
“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,” Mark Berger, MD, Actinium’s chief medical officer, said in a press release. “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,” he added. “The result is significant DNA damage that can have a profound anti-tumor effect.
“We have great excitement for the third and final cohort and hope to improve on the already encouraging results we have seen thus far.”
Actinium also plans to start a Phase 1 dose-escalating trial in newly diagnosed AML patients with intermediate or high-risk cytogenetic or molecular markers, to see if they would benefit from a combination of Actimab-A plus the chemo regimen 7+3 (7 days of cytarabine and 3 days of the anthracycline daunorubicin).
This regimen is standard of care for patients with newly diagnosed AML who tolerate intensive chemotherapy.
If successful, the study could make Actimab-A a potential treatment for newly diagnosed AML patients, and support the combination of ARCs with other treatment mechanisms to produce better clinical results.
Actimab-A is also being studied in a Phase 1/2 combination trial (NCT03867682) with the targeted therapy Venclexta in patients with relapsed or refractory AML. The open-label trial is currently recruiting up to 38 people at its one site in Kentucky.
“ARCs may enable us to deliver the validated modality of radiation to cancers at a cellular level without exposing patients to toxicities that would come from delivering radiation via external beam to diffuse hematologic malignancies,” Joseph Jurcic, MD, professor at Columbia University Herbert Irving Comprehensive Cancer Center, said in another press release.
“There is a strong mechanistic rationale for adding Actimab-A to 7+3 that we believe will result in higher response rates and more durable complete remissions without additive toxicities,” he added.