Leukemia Drug Put on Clinical Hold After Four Deaths

FDA concerned about hepatotoxicity risk

Seattle Genetics, a biotechnology company based in Washington, has received notice from the FDA that a clinical hold or partial clinical hold has been placed on several early- stage trials of vadastuximab talirine in subjects with acute myeloid leukemia (AML). The clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with vadastuximab and who received allogeneic stem cell transplant either before or after treatment. Six patients have been identified with hepatotoxicity, including several cases of veno-occlusive disease, with four deaths.

Vadastuximab talirine is an investigational antibody–drug conjugate targeted to the CD33 transmembrane receptor. CD33 is expressed on most AML and myelodysplastic syndrome blast cells. A CD33 engineered cysteine antibody is linked to a DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology. Vadastuximab is designed to be stable in the bloodstream and to release its cell-killing PBD agent after internalization into CD33-expressing cells.

A phase 1/2 study of vadastuximab monotherapy in AML patients after pre- and post-allogeneic transplant has been placed on full clinical hold. In addition, two phase 1 trials have been placed on partial clinical hold (no new enrollment; existing patients may continue treatment with reconsent). These studies involve vadastuximab monotherapy, including a subset of older AML patients in combination with hypomethylating agents, and vadastuximab combination treatment with 7+3 chemotherapy in newly diagnosed younger AML patients. No new studies will be initiated until the clinical holds are lifted.

Other ongoing studies of vadastuximab, including a phase 3 study in older AML patients and a phase 1/2 study in subjects with myelodysplastic syndrome, are proceeding with enrollment.

Vadastuximab was granted orphan drug status by the FDA for the treatment of patients with AML. This designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

Source: Seattle Genetics; December 27, 2016.