Flotetuzumab for AML passes phase 1 test

MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.

Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).

In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.

The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”

In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.

“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.

“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.

As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.

“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”

Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.

MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.

MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.

Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).

In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.

The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”

In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.

“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.

“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.

As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.

“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”

Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.

MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.

MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.

Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).

In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.

The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”

In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.

“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.

“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.

As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.

“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”

Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.

MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.