The FDA has placed a hold on several mid- and early-stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML) being conducted by Seattle Genetics following the deaths of four patients, the company announced.
A Phase I/II trial of SGN-CD33A monotherapy in pre- and post-allogeneic transplant AML patients has been placed on full clinical hold, while two Phase I trials of the candidate were placed on partial clinical holds (no enrollment of new patients) though existing patients may continue treatment with reconsent.
The two trials placed on partial hold were a study of SGN-CD33A monotherapy, including a subset of older AML patients in combination with hypomethylating agents, and an SGN-CD33A combination treatment with 7+3 chemotherapy in newly diagnosed younger AML patients.
The clinical holds will be in place pending an evaluation of the potential risk of hepatotoxicity in patients who were treated with SGN-CD33A and received allogeneic stem cell transplant, either before or after treatment.
According to Seattle Genetics, the four deaths were among six patients who have been identified with hepatotoxicity, including several cases of veno-occlusive disease.
“Seattle Genetics is working diligently with the FDA to determine whether there is any association between hepatotoxicity and treatment with SGN-CD33A, to promptly identify appropriate protocol amendments for patient safety and to enable continuation of these trials,” the company said in a statement.
Overall, more than 300 patients have been treated with SGN-CD33A in various clinical trials. No new studies of SGN-CD33A will be initiated until the clinical holds are lifted, Seattle Genetics added.
The clinical holds will not affect other ongoing trials of SGN-CD33A, including the Phase III CASCADE trial in older AML patients and a Phase I/II trial in myelodysplastic syndrome (MDS). Those studies are proceeding with enrollment, Seattle Genetics said.
SGN-CD33A is a CD33-targeting antibody-drug conjugate (ADC) candidate that targets CD33, which is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA-binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb).
According to Seattle Genetics, the ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD33-expressing cells.
SGN-CD33A has been granted the Orphan Drug designation of both the FDA and the European Commission for the treatment of AML.