Following discussions with the U.S. Food and Drug Administration (FDA), MacroGenics is planning for a single-arm clinical trial that supports the approval of its investigational molecule flotetuzumab for the treatment of people with acute myeloid leukemia (AML) who failed to respond to initial therapy.
The trial will include 200 individuals who either failed to achieve complete remission with intensive chemotherapy or who relapsed less than six months after entering remission. These patient populations historically have poor responses to subsequent chemotherapy, with fewer than 10% ultimately achieving remission.
The primary goal is to determine the proportion of people achieving complete remission, with full or partial recovery of blood parameters, or hematological recovery. Secondary measures include duration of response.
Pending positive results, flotetuzumab may receive accelerated approval from the FDA. However, full approval will require that a confirmatory trial supports flotetuzumab’s benefits over standard-of-care approaches.
“Patients with AML who are refractory to induction [a first] therapy or relapse early after an initial response have limited treatment options,” Scott Koenig, MD, PhD, president and CEO of MacroGenics, said in a press release.
“Clinical and translational data suggest that such refractory AML patients may be responsive to immunotherapy with flotetuzumab,” he added. “We are very pleased to advance our first DART molecule into a pivotal study with an opportunity to address a significant unmet need.”
AML patients who fail to achieve complete remission or experience early relapse after induction — or a first course of — chemotherapy are difficult to treat. They make up 40% of all newly diagnosed patients, but only 14% will achieve remission with conventional chemotherapy. Subsequent salvage attempts are even less effective.
It is thought that AML arises from a population of leukemic stem cells that are resistant to chemotherapeutic agents and characterized by high levels of the CD123 receptor. In AML, the presence of these CD123-positive leukemia cells is associated with poor prognoses.
Flotetuzumab, made with MacroGenics’ dual affinity re-targeting (DART) platform, is an antibody-based molecule that targets both CD123 on leukemia cells and the CD3 receptor on immune T-cells. Its goal is to redirect these immune cells — which have the ability to fight cancer — to kill CD123-positive cells.
The ongoing Phase 1/2 trial is investigating flotetuzumab as a treatment for adults who failed two or more induction attempts or whose disease relapsed within the first six months. The trial is recruiting at 26 clinical sites in the U.S. and Europe, for an estimated total enrollment of 179 patients.
The researchers recently presented data from the first 30 patients receiving the recommended dose of flotetuzumab. Among the participants were 24 individuals who had failed two or more induction chemotherapy regimens, and six who saw their disease recur after a short remission period (median 32 days).
The findings showed that nine patients (30%) achieved remission, including five (16.6%) with a total hematological recovery, and eight (26.7%) with full or partial hematological recovery. The remaining patient on remission had an incomplete hematological recovery.
Flotetuzumab was generally well-tolerated, despite all patients experiencing cytokine release syndrome — a result of excessive immune activation – or infusion-related reactions. These conditions, however, were mild-to-moderate in most patients and resolved after a short period.
The treatment candidate also is being investigated in combination with chemotherapy in a Phase 1 trial (NCT04158739) for AML patients younger than 21, and in a Phase 2 trial (NCT03739606) for adolescents and adults (ages 15 or older) with relapsed or refractory blood cancers other than AML.
In addition, MacroGenics has initiated a Phase 1/2 trial outside the U.S. to study the therapy, in combination with its PD-1 inhibitor MGA012, in relapsed or refractory AML. That study was started after MacroGenics demonstrated that flotetuzumab may enhance responses to immune checkpoint inhibitors.
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