Novel PI3Kδ Inhibitor in Relapsed or Refractory Hematologic Malignancies
In a phase I trial reported in The Lancet Oncology, Burris et al determined the phase II dose of the next-generation PI3Kδ inhibitor umbralisib and found evidence of the agent’s activity in relapsed or refractory hematologic malignancies. Umbralisib exhibits improved PI3K isoform selectivity and also inhibits casein kinase-1ε, a regulator of protein translation.
Study Details
In the dose-escalation study, conducted at seven U.S. sites, 90 adult patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin lymphoma who had received at least 1 previous line of therapy received once-daily oral umbralisib at 50 to 1,800 mg in a fasting state or a micronized formulation at 200 to 1,800 mg in a fed state between January 2013 and January 2016. In August 2014, all patients remaining on study were switched to 800 mg of the micronized formulation.
Adverse Events
Median duration of treatment and follow-up was 133 days. The most common adverse events of any grade were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3 or 4 adverse events were neutropenia (13%), anemia (9%), and thrombocytopenia (7%). Serious adverse events considered at least possibly related to umbralisib occurred in 8%, consisting of pneumonia in 3%, lung infection in 1%, febrile neutropenia in 1%, and colitis in 2%.
The maximum tolerated dose was 1,200 mg of the micronized formulation, and 800 mg of the micronized formulation was selected as the recommended phase II dose. Both cases of colitis occurred at a dose > 800 mg/d.
Response Rates
Overall, objective response was observed in 33 (37%) of the 90 patients, including 17 (85%) of 20 patients with relapsed/refractory chronic lymphocytic leukemia (6 of 8 with high-risk cytogenetic features), and 9 (53%) of 17 with follicular lymphoma. No responses were observed among 8 patients who received the original nonmicronized formulation at a dose < 800 mg/d.
The investigators concluded, “Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase I study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting.”
The study was funded by TG Therapeutics.
Owen A. O’Connor, MD, of the Center for Lymphoid Malignancies, Columbia University Medical Center, is the corresponding author for The Lancet Oncology article.
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