The investigational next-generation oral PI3Kδ inhibitor umbralisib (TGR-1202) was well-tolerated and exhibited early signs of clinical activity among patients with relapsed or refractory follicular lymphoma, chronic lymphocytic leukemia, and other lymphomas, according to findings from a first-in-human, open-label, phase I dose-escalation clinical trial published in The Lancet Oncology.“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,” reported lead study author Howard A. Burris III, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, and coauthors.

The phosphatidylinositol 3-kinase (PI3K) cell membrane enzyme pathway is involved in B-cell receptor signaling, differentiation, growth, survival, and activation. Idelalisib, the first PI3K isoform δ signaling (PI3Kδ) pathway inhibitor to be approved by the US Food and Drug Administration, is indicated as a salvage therapy following other treatment options, because of late-emerging life-threatening side effects including immune-related colitis and pneumonitis, and pneumonia.

The structure and selectivity of umbralisib are different from other PI3Kδ inhibitors. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1Ɛ.

The study team enrolled 90 patients between January 2013 and January 2016 for treatment with self-administered umbralisib tablets (once daily in 28-day cycles) for relapsed or treatment-refractory chronic lymphocytic leukemia (n = 24), follicular lymphoma (n = 22), other B-cell non-Hodgkin lymphomas (n = 27), Hodgkin lymphoma (n = 11) and T-cell lymphoma or hairy-cell leukemia (n = 3). Most patients (58%) had previously received at least three lines of therapy. Of the patients in this safety cohort, only 73 were evaluable for clinical activity.

The most common adverse events were diarrhea (43%), nausea (42%), and fatigue (31%), but few patients experienced grade 3 or higher adverse events; 3% of patients experienced grade 3 diarrhea. Thirteen percent had respiratory-tract infections and 8% suffered pneumonia.

There were two cases of steroid-ameliorated colitis among patients receiving higher doses of umbralisib. One of those patients had febrile neutropenia.

The maximum tolerated dose was 1,200 mg. The authors determined that the phase-II trial dose should be 800 mg, a dose below that administered to the two patients who experienced colitis.

Thirty-seven percent of the 90 patients in the safety cohort achieved an objective response, including 53% of patients with relapsed or refractory follicular lymphoma.

“The clinical activity and safety reported with umbralisib in this study is encouraging,” commented Jacqueline C Barrientos, MD, of the Feinstein Institute for Medical Research, Zucker School of Medicine, in New Hyde Park, New York, in an independent commentary published alongside the study. “Given the promising safety data from this study, patients might be able to continue taking umbralisib for a prolonged period.”

Fourteen percent of the patients have been treated with umbralisib for more than 2 years, but longer follow-up is needed to determine if remissions can be sustained without the late side-effects seen with other PI3Kδ inhibitors.

“As was learned previously from idelalisib use, some toxicities might only develop after prolonged exposure to the drug-colitis developed after 7 months of idelalisib therapy,” Dr. Barrientos wrote.

The study was funded by TG Therapeutics.