FDA Stops Multiple Trials for Acute Myeloid Leukemia Drug

Several phase 1 trials of vadastuximab talirine (SGN-CD33A) for acute myeloid leukemia (AML) were placed on hold by the U.S. Food and Drug Administration (FDA), according to Seattle Genetics, the manufacturer of the antibody-drug conjugate.

The clinical holds followed the deaths of four patients who were treated with vadastuximab talirine along with allogeneic stem cell transplant (ASCT) either prior to or following treatment. Specifically, the FDA wants to assess the risk of hepatotoxicity, as the four patients who died had veno-occlusive disease. Two other patients also had hepatotoxicity.

A full clinical hold has been placed on a phase 1/2 study of single-agent vadastuximab talirine in patients with AML, both pre- and post-ASCT. Two other phase 1 trials received partial clinical holds, meaning further enrollment is halted but enrolled patients who consent can continue therapy.

One of the phase 1 trials is examining the antibody-drug conjugate in combination with hypomethylating agents in older patients with AML, and the other study is assessing the combination of vadastuximab talirine with 7+3 chemotherapy in younger or newly diagnosed AML patients.

Vadastuximab talirine works by binding to the CD33 transmembrane receptor expressed in approximately 90 percent of patients with AML. Seattle Genetics is collaborating with the FDA to assess the potential link between hepatotoxicity and vadastuximab talirine.

Phase 1b data presented at the 2016 ASH Annual Meeting showed rapid and deep remissions with vadastuximab talirine in patients with AML. Forty-patients had been treated in the ongoing study. The median age was 45.5 years with an ECOG performance status of 0 to 1; 17 percent of patients had secondary AML, 50 percent had intermediate-risk karyotypes and 36 percent adverse karyotypes.

Patients received escalating doses of vadastuximab talirine in combination with 7+3 induction (cytarabine 100 mg/m² and daunorubicin 60 mg/m²) on days one and four of a 28-day treatment cycle, and responses were assessed on days 15 and 28. A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine. The primary objectives of the study were to assess safety, tolerability, and any early signs of antileukemic activity.

Seventy-six percent of patients achieved a response, with 60 percent achieving complete remission and 17 percent achieving remission with incomplete blood count recovery.

The investigators observed no evidence of increased toxicity or mortality with the addition of vadastuximab talirine, and the rates of adverse events (AEs) were similar to what would be expected with standard chemotherapy alone. The incidence of grade 3/4 hematologic events was no higher than typical in patients receiving the 7+3 regimen alone.

No patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage, although grade 3 or higher liver function test abnormalities were observed in one patient. The most commonly reported grade 1/2 nonhematologic AEs were nausea (55 percent), diarrhea (33 percent) and constipation (31 percent).

Overall, more than 300 patients in clinical studies have received vadastuximab talirine across several settings. Enrollment continues in other ongoing trials, including the phase 3 CASCADE study in older patients with AML and a phase 1/2 trial of patients with myelodysplastic syndrome