FDA Places Holds on Several Vadastuximab Talirine Trials in AML

Several phase I trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML) have been placed on hold by the FDA, according to Seattle Genetics, the manufacturer of the antibody-drug conjugate.

The clinical holds followed the deaths of 4 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 4 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 I trials received partial clinical holds, meaning further enrollment is halted but enrolled patients who consent can continue therapy.

One of the phase I 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% of patients with AML. Seattle Genetics is collaborating with the FDA to assess the potential link between hepatotoxicity and vadastuximab talirine.

Phase Ib 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% of patients had secondary AML, 50% had intermediate-risk karyotypes and 36% adverse karyotypes.

Patients received escalating doses of vadastuximab talirine in combination with 7+3 induction (cytarabine 100 mg/m²and daunorubicin 60 mg/m²) on days 1 and 4 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% achieving complete remission and 17% 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 liver function test abnormalities were observed in 1 patient. The most commonly reported grade 1/2 nonhematologic AEs were nausea (55%), diarrhea (33%), and constipation (31%).

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

Reference:

Erba HP, Levy MY, Vasu S, et al. A phase 1b study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 906.