The study, “Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study,” appeared in the journal The Lancet Oncology.
Umbralisib, previously known as TGR-1202, is a novel, oral inhibitor of phosphatidylinositol 3-kinase (PI3K), a family of enzymes important for the proliferation and survival of B‐cells. Specifically, umbralisib inhibits the isoform (variant) p110 delta with better selectivity than other PI3K delta inhibitors.
The compound also inhibits casein kinase-1 epsilon, which regulates diverse cellular events, including protein production and DNA repair.
The Phase 1 trial (NCT01767766) determined the safety and preliminary activity profile of umbralisib in 90 adult patients at seven clinics in the U.S. Participants had relapsed or refractory B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and various forms of lymphoma — non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and peripheral T-cell lymphoma.
Patients took once-daily oral tablets of umbralisib in 28-day cycles. The compound was given in increasing doses — from 50 to 1,800 mg in patients in a fasting state, or 200 to 1,800 mg in those in a fed state. The mean duration of treatment was 133 days.
Results showed that umbralisib was well-tolerated. The most common severe or life-threatening adverse events were low levels of neutrophils, anemia, and low levels of platelets. Adverse events frequently associated with other PI3K delta inhibitors, including pneumonia and colitis, were limited. Two cases of colitis occurred at a dose higher than the recommended dose (800 mg) for phase 2.
Umbralisib reduced disease burden in 62% of patients, as assessed by computed tomography (CT) scans. Partial or complete responses were seen in 33 of the 90 patients (37%).
Patients with relapsed or refractory CLL benefited most from the treatment — 85% achieved a partial response and 15% had their disease stabilized.
Among those with follicular lymphoma, the response rate was 53%, with two patients having a full tumor eradication. Also, 31% of patients with diffuse large B-cell lymphoma responded to the therapy, and 15% had disease stabilization.
“Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies,” the researchers wrote.
“The safety profile of umbralisib in this Phase 1 study was distinct from that of other (PI3K delta) inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis,” they said.
“Several patients from this Phase 1 study are still on study today, approaching five years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent,” Howard A. Burris, MD, the study’s lead author, said in a press release.
Results from this trial set the stage for the ongoing Phase 3 trial (NCT02612311) in patients with untreated and previously treated CLL — UNITY-CLL — and the Phase 2/3 study (NCT02793583) in patients with previously treated NHL — UNITY-NHL. The UNITY-NHL trial is currently recruiting patients (more information here).
“With over 1,000 patients treated with umbralisib to date, we and the investigators believe umbralisib is a differentiated, active and more selective PI3K delta inhibitor that exhibits a favorable safety profile as compared to prior generation molecules,” said Michael S. Weiss, executive chairman and CEO of TG Therapeutics.