Clinical Holds on Vadastuximab Talirine Trials in AML Lifted by FDA

Clinical holds on several phase I trials of vadastuximab talirine in acute myeloid leukemia have been lifted by the FDA.

Clinical holds on several phase I trials of vadastuximab talirine (SGN-CD33A) in acute myeloid leukemia (AML) have been lifted by the FDA, according to Seattle Genetics, the manufacturer of the antibody-drug conjugate.

In late December 2016, the FDA enacted the clinical holds following the deaths of 4 patients who were treated with vadastuximab talirine along with allogeneic stem cell transplant (ASCT) either prior to or following treatment. Specifically, the FDA wanted to assess the risk of hepatotoxicity, as the 4 patients who died had veno-occlusive disease.

A full clinical was placed on a phase 1/2 study of single-agent vadastuximab talirine in patients with AML, both pre- and post-ASCT. Two other phase I trials received partial clinical holds, meaning further enrollment was halted but enrolled patients were allowed to continue therapy. One of the phase I trials is examining the antibody-drug conjugate in combination with hypomethylating agents in older patients with AML, and the other study is assessing the combination of vadastuximab talirine with 7+3 chemotherapy in younger or newly diagnosed AML patients.

“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, MD, chief medical officer and executive vice president, Research and Development at Seattle Genetics, said in a statement.

“We will resume two phase I trials in AML and plan to initiate a randomized phase II trial during 2017 evaluating vadastuximab talirine in combination with standard of care chemotherapy in frontline, younger AML patients. In addition, we are continuing to enroll our ongoing phase III randomized CASCADE trial in frontline older AML patients and our phase 1/2 trial in frontline high-risk myelodysplastic syndrome,” added Drachman.

Specifically, Seattle Genetics is resuming the phase I trial combining vadastuximab talirine with hypomethylating agents in older AML patients, as well as the phase I trial examining the antibody-drug conjugate in combination with 7+3 chemotherapy in newly diagnosed or younger AML patients. The company does not plan to continue the phase I/II trial of single-agent vadastuximab talirine in pre- and post-allogeneic transplant AML patients. Across all vadastuximab talirine studies, Seattle Genetics plans to incorporate additional measures to mitigate risk, including revising both the eligibility criteria and the protocols for halting treatment due to veno-occlusive disease.

Vadastuximab talirine works by binding to the CD33 transmembrane receptor expressed in approximately 90% of patients with AML. Phase Ib data presented at the 2016 ASH Annual Meeting showed rapid and deep remissions with vadastuximab talirine in patients with AML. 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/m2and 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.

Seventy-six percent of patients achieved a response, 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.