Photo courtesy of the
University of Minnesota
A bispecific ligand-directed diphtheria toxin known as DT2219 shows promise for treating patients with relapsed/refractory B-cell malignancies, according to researchers.
DT2219 produced responses in 2 of 25 patients analyzed in a phase 1 study. The maximum tolerated dose of DT2219 was not reached, although 2 patients experienced dose-limiting toxicities.
“In this phase 1 trial, we found a safe dose of the drug that has biological activity,” said Daniel Vallera, PhD, of the University of Minnesota in Minneapolis.
“We are planning a phase 2 trial with this drug. It will focus on giving more cycles of treatment, which we believe will dramatically enhance the response rates.”
Dr Vallera and his colleagues detailed the phase 1 results in Clinical Cancer Research.
To develop DT2219, the researchers chose 2 antibody fragments that each selectively bind to CD19 and CD22. They used genetic engineering to attach these two antibodies to the bacterial diphtheria toxin.
When the antibody fragments bind to the two targets on the cancer cell, the entire drug enters the cell, and the toxin kills the cell.
To test DT2219, the researchers enrolled 25 patients with chemo-refractory pre-B acute lymphoblastic leukemia (n=10), chronic lymphocytic leukemia (n=5), or non-Hodgkin lymphoma (n=10). All tumors had CD19 and/or CD22 proteins.
Patients had received a median of 3 prior therapies (range, 2 to 5), and 8 patients had undergone an unsuccessful stem cell transplant (5 autologous and 3 allogeneic).
Patients received DT2219 intravenously over 2 hours every other day for 4 total doses. The dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in 9 dose cohorts until a dose-limiting toxicity occurred.
All but 1 patient received a single course of DT2219. That patient received a second, 4-dose course after attaining a partial response.
Outcomes
The 12 patients who received doses ranging from 0.5 mg/kg/day to 20 mg/kg/day had minimal or no adverse events (AEs). But all 13 patients who received 4 doses of DT2219 at 40 mg/kg or greater every other day experienced treatment-related AEs.
Grade 1-2 treatment-related AEs included capillary leak syndrome (n=7), ALT/AST elevation (n=4), fatigue (n=3), fever (n=3), hypokalemia (n=2), hypoalbuminemia (n=1), hearing loss (n=1), hypocalcemia (n=1), anemia (n=1), and vomiting (n=1).
Grade 3-4 treatment-related AEs were thrombocytopenia (n=2), neutropenia (n=1), neutropenic fever (n=1), capillary leak syndrome (n=1), hypokalemia (n=1), and leg weakness (n=1). The grade 3 leg weakness and grade 3 capillary leak syndrome were dose-limiting toxicities.
The maximum tolerated dose was not reached, but clinical responses occurred between doses of 40 to 80 µg/kg.
All 25 patients were evaluable for response, but only 9 patients in the highest dose cohorts had measurable drug levels.
Two patients had durable, objective responses. One patient had chronic lymphocytic leukemia, and the other had diffuse large B-cell lymphoma. The latter patient’s response was a complete remission that occurred after 2 treatment cycles.
“We were surprised that the drug was effective enough to entirely eliminate the cancer in one of our patients,” Dr Vallera said. “Further, we expected the patients to make antibodies against the bacterial toxin and, thus, reject our drug. Surprisingly, this did not occur in the majority of our patients [70%].”
“We need to study more patients to understand why they did not produce neutralizing antibodies. However, we also have been working to create a less immunogenic form of the toxin for the next-generation drug.”
“Another important fact about our drug is that it was home-grown, meaning there was no commercial partner, which is rare. The drug was funded mostly with private donations, including individuals that have lost loved ones to cancer.”
