The FDA has lifted the clinical hold it placed on early- to mid-stage trials of Seattle Genetics’ cancer candidate vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML) following the deaths of four patients.
Seattle Genetics said yesterday it will resume two Phase I trials affected by the clinical hold. One is a study of vadastuximab talirine monotherapy and combination treatment with hypomethylating agents in both newly diagnosed and relapsed AML patients. The other trial is designed to assess a vadastuximab talirine combination treatment with standard of care, or 7+3 chemotherapy, in newly diagnosed younger AML patients.
Not being resumed is a Phase I/II trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant AML patients. The company cited “the challenges of developing therapies in this specific setting,” without elaborating.
The Phase I/II study was placed on full clinical hold, while the Phase I trials were placed on partial clinical hold consisting of no enrollment of new patients, though existing patients were allowed to continue treatment with reconsent.
The hold was placed in December following the four patient deaths, which were among six patients identified with hepatotoxicity, including several cases of veno-occlusive disease (VOD).
“The clinical hold on our early-stage vadastuximab talirine clinical trials has been resolved through a comprehensive analysis of the clinical data from over 300 patients treated to date, evaluation by an independent committee of clinical experts, collaborative interactions with the FDA, and protocol amendments designed to further enhance patient safety,” Jonathan Drachman, M.D., CMO and evp, research and development at Seattle Genetics, said in a statement.
The company said it will implement additional risk mitigation measures in all vadastuximab talirine studies, including revised eligibility criteria and stopping rules for VOD.
Seattle Genetics also said it will launch this year a new trial of vadastuximab talirine, a Phase II study evaluating the candidate in combination with standard of care 7+3 chemotherapy in frontline, younger AML patients.
Not affected by the clinical hold, and still enrolling patients, are two other ongoing trials of vadastuximab talirine—the Phase III CASCADE trial in older AML patients and a Phase I/II trial in myelodysplastic syndrome (MDS).
Vadastuximab talirine 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.
Vadastuximab talirine has been granted the Orphan Drug designation of both the FDA and the European Commission for the treatment of AML.