Seattle Genetics said today it was halting enrollment in all clinical trials assessing its cancer candidate vadastuximab talirine (SGN-CD33A). The trials include a Phase III study in frontline older acute myeloid leukemia (AML) patients where patients died, which is being halted altogether, and an ongoing Phase I/II study in frontline high-risk myelodysplastic syndrome (MDS).
The company said it acted in consultation with the Phase III study’s Independent Data Monitoring Committee (IDMC) following a review of unblinded data on Friday. The data, according to Seattle Genetics, indicated a higher rate of deaths, including fatal infections, in the vadastuximab talirine arm compared with the control arm.
“This is a disappointing and unexpected result for the CASCADE trial. Patient safety is our highest priority, and we will closely review the data and evaluate next steps,” Seattle Genetics president and CEO Clay Siegall, Ph.D., said in a statement.
Seattle Genetics also said it will consult with the FDA to determine future plans for its vadastuximab talirine development program.
Based on available data, the safety issues related to CASCADE did not appear related to hepatotoxicity, the company added. Four patients among six identified with hepatotoxicity died last year during a Phase I/II trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant AML patients.
As a result, the FDA imposed a full clinical hold in December on that trial—which Seattle Genetics opted not to resume—as well as partial clinical holds on several early- to mid-stage trials of vadastuximab talirine that were lifted in March.
CASCADE was a randomized, double-blind, placebo-controlled study designed to assess vadastuximab talirine in combination with the hypomethylating agents (HMAs) azacitidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.
The statement offered no reason for suspending the Phase I/II study in MDS.
Vadastuximab talirine is designed to target CD33, a protein expressed on most AML and MDS blast cells. Vadastuximab talirine uses Seattle Genetics’ proprietary antibody–drug conjugate (ADC) technology, which consists of a novel CD33-directed antibody conjugated to two molecules of a highly potent DNA crosslinking agent called a PBD (pyrrolobenzodiazepine) dimer via a site-specific conjugation technology with engineered cysteines (EC-mAb).
Seattle Genetics reasons that PBD dimers are significantly more potent than systemic chemotherapeutic drugs, with the site-specific conjugation technology allowing for uniform drug-loading of the cell-killing PBD agent to the CD33-directed antibody. The ADC is designed to be stable in the bloodstream and to release its potent DNA-binding agent when internalized by CD33-expressing cells.
Vadastuximab talirine was granted Orphan Drug Designation by both the FDA and the European Commission for the treatment of AML.
Dr. Siegall signaled that Seattle Genetics will refocus on other pipeline candidates, including lead product Adcetris® (brentuximab vedotin), enfortumab vedotin (ASG-22ME), and SGN-LIV1A.
He said the company still plans to report data from its Adcetris Phase III ECHELON-1 trial in frontline Hodgkin's lymphoma—something Seattle Genetics said in April would occur later this year.
Dr. Siegall added that the company was on track to advance enfortumab vedotin into a pivotal trial in metastatic urothelial cancer in the second half of this year. Enfortumab vedotin is being developed through a collaboration with Astellas.