The US Food and Drug Administration (FDA) has placed holds on 3 early stage trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML).
A phase 1/2 trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant patients has been placed on full clinical hold.
This means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.
Two phase 1 trials of vadastuximab talirine have been placed on partial clinical hold. This means no new subjects can be enrolled, but existing patients may continue treatment with re-consent.
In one of the trials on partial hold, researchers are investigating vadastuximab talirine alone and in combination with hypomethylating agents in AML patients who either relapsed after induction/consolidation or declined treatment with high-dose induction/consolidation.
In the other trial on partial hold, researchers are testing vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed AML patients. Results from this trial were presented at the 2016 ASH Annual Meeting.
All 3 clinical holds were initiated to evaluate the potential risk of hepatotoxicity in patients who were treated with vadastuximab talirine and received allogeneic stem cell transplant either before or after treatment.
There have been 6 patients with hepatotoxicity, including several cases of veno-occlusive disease, with 4 fatal events.
Seattle Genetics, Inc., the company developing vadastuximab talirine, said it is working with the FDA to determine whether there is any association between hepatotoxicity and treatment with vadastuximab talirine to identify appropriate protocol amendments for patient safety and to enable continuation of these trials.
No new studies of vadastuximab talirine will be initiated until the clinical holds are lifted.
Seattle Genetics’ other ongoing trials of vadastuximab talirine, including the phase 3 CASCADE trial in older AML patients and phase 1/2 trial in patients with myelodysplastic syndrome (MDS), are proceeding with enrollment.
Overall, more than 300 patients have been treated with vadastuximab talirine in clinical trials across multiple treatment settings.
Vadastuximab talirine is an investigational antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb).
PBD dimers are said to be significantly more potent than systemic chemotherapeutic drugs, and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its PBD agent upon internalization into CD33-expressing cells.
