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AML cells
The US Food and Drug Administration (FDA) has lifted the clinical hold placed on 3 trials of vadastuximab talirine (SGN-CD33A), an antibody-drug conjugate targeting CD33, in acute myeloid leukemia (AML).
Last December, 1 trial was placed on full clinical hold (enrollment was halted and no further dosing of subjects was allowed), and 2 were placed on partial hold (enrollment was halted, but existing patients could continue treatment with re-consent).
All 3 of the holds were due to the potential risk of hepatotoxicity in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with vadastuximab talirine.
In particular, the holds were in response to 6 cases of hepatotoxicity, including several cases of veno-occlusive disease (VOD), with 4 fatal events.
At the time the holds were announced, Seattle Genetics, Inc., the company developing vadastuximab talirine, said it was working with the FDA to determine whether there is an association between hepatotoxicity and treatment with the drug.
The company analyzed data from more than 350 patients treated with vadastuximab talirine and found no such association.
The rate of VOD they observed was “within the background rate of VOD in AML patients receiving allo-transplant,” according to Clay B. Siegall, PhD, president, chief executive officer, and chairman of the board at Seattle Genetics.
Dr Siegall said the company would not disclose the exact rate of VOD in these trials.
Resuming trials
As Seattle Genetics found no evidence to suggest that vadastuximab talirine increased the risk of hepatotoxicity, the FDA lifted the clinical holds on all 3 trials. The 2 trials placed on partial hold will continue, but the trial placed on full hold will not.
One of the trials that will continue is a phase 1 study of vadastuximab talirine alone and in combination with hypomethylating agents in both newly diagnosed and relapsed AML patients.
The other trial is a phase 1 study of vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients. (Results from this trial were presented at the 2016 ASH Annual Meeting.)
Cancelled trial
The trial that will not resume is a phase 1/2 study of vadastuximab talirine monotherapy pre- and post-allogeneic HSCT in patients with relapsed, chemo-resistant AML.
Seattle Genetics said it will not continue with this trial because of the challenges of developing therapies in this specific setting.
“It’s a very small group of patients, and we’re going to focus on the 3 biggest groups of patients [older and younger patients newly diagnosed with AML and patients with myelodysplastic syndromes] so we can really impact AML in the biggest way,” Dr Siegall said.
He noted that this decision does not prevent patients from undergoing HSCT after receiving vadastuximab talirine.
In the phase 1/2 trial, patients received vadastuximab talirine directly before HSCT, a practice that will not continue. However, patients can undergo HSCT as long as the transplant doesn’t occur immediately after treatment with vadastuximab talirine.
Moving forward
Two other trials of vadastuximab talirine were not affected by the clinical holds and have continued to enroll patients.
One is CASCADE, a randomized, phase 3 trial of vadastuximab talirine as front-line therapy in older AML patients. The other is a phase 1/2 trial of vadastuximab talirine as front-line therapy in patients with myelodysplastic syndromes.
Seattle Genetics is also planning to begin a randomized, phase 2 trial comparing 7+3 chemotherapy alone to 7+3 in combination with vadastuximab talirine in younger patients with previously untreated AML. The company plans to start the trial later this year.
Going forward, additional risk mitigation measures will be implemented in all vadastuximab talirine studies, including revised eligibility criteria and stopping rules for VOD.
Specifically, trials will not be stopped if the incidence of VOD is considered within the normal range, and an adjudication committee consisting of 2 experts will be tasked with verifying reports of VOD.
In addition, patients with liver cirrhosis due to alcohol abuse are no longer eligible for trials of vadastuximab talirine.
