Phase III Vadastuximab Talirine Frontline AML Trial Discontinued

Clay Siegall, PhD, Seattle Genetics president and CEO

Clay Siegall, PhD

Seattle Genetics has stopped the phase III CASCADE trial of frontline vadastuximab talirine (SGN-CD33A) for patients with acute myeloid leukemia following a recommendation from an independent data monitoring committee.

The independent panel observed a higher rate of deaths, including fatal infections, in the vadastuximab talirine arm compared with the control arm after reviewing unblinded data on June 16. The company said safety concerns in the trial do not appear related to hepatotoxicity.

Seattle Genetics is suspending patient enrollment and treatment in all its vadastuximab talirine clinical trials, including the ongoing phase 1/2 clinical trial in frontline high-risk myelodysplastic syndrome. What this means for the future of the company’s vadastuximab talirine development program is unclear; the company said it will work with the FDA to determine its next steps.

“This is a disappointing and unexpected result for the CASCADE trial,” Clay Siegall, PhD, Seattle Genetics president and CEO, said in a prepared statement. “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.”

CASCADE was a randomized, double-blind, placebo-controlled study evaluating vadastuximab talirine in combination with the hypomethylating agents (HMAs) azacitidine (Vidaza) or decitabine (Dacogen) versus an HMA alone in older patients with newly diagnosed AML. Vadastuximab talirine is a novel investigational antibody-drug conjugate targeted to CD33, a transmembrane receptor expressed in approximately 90% of patients with AML.

In March, the FDA lifted holds placed on phase I trials of vadastuximab talirine in AML. The agency instituted clinical holds on 3 phase I trials in December 2016 following the deaths of 4 patients who were treated with vadastuximab talirine along with allogeneic stem cell transplant either prior to or following treatment. The FDA specifically wanted to assess the risk of hepatotoxicity because the patients who died all had veno-occlusive disease.

The agency placed a full clinical hold on a phase 1/2 study of single-agent vadastuximab talirine in patients with AML and partial holds on 2 phase I trials, 1 examining the antibody-drug conjugate in combination with hypomethylating agents in older patients with AML and the other assessing the combination of vadastuximab talirine with 7+3 chemotherapy in younger or newly diagnosed AML patients.

Results from the latter study were presented at last year’s ASH Annual Meeting, and vadastuximab talirine was associated with rapid and deep remissions. Forty-patients had been treated in the ongoing study. The median age was 45.5 years with an ECOG performance status of 0 to 1; 17% of patients had secondary AML, 50% had intermediate-risk karyotypes and 36% adverse karyotypes.

Patients received escalating doses of vadastuximab talirine in combination with 7+3 induction (cytarabine 100 mg/m² and daunorubicin 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle, and responses were assessed on days 15 and 28. A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine. The primary objectives of the study were to assess safety, tolerability, and any early signs of antileukemic activity.

The response rate was 76%, with 60% achieving complete remission and 17% achieving remission with incomplete blood count recovery.

The investigators observed no evidence of increased toxicity or mortality with the addition of vadastuximab talirine, and the rates of adverse events (AEs) were similar to what would be expected with standard chemotherapy alone. The incidence of grade 3/4 hematologic events was no higher than typical in patients receiving the 7+3 regimen alone.

No patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage, although grade ≥3 liver function test abnormalities were observed in 1 patient. The most commonly reported grade 1/2 nonhematologic AEs were nausea (55%), diarrhea (33%), and constipation (31%).

Erba HP, Levy MY, Vasu S, et al. A phase 1b study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 906.