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Umbralisib Shows Early Promise in CLL and Lymphoma

Jason Harris
Published: Wednesday, Feb 21, 2018

Owen A. O'Connor, MD, PhD
Owen A. O'Connor, MD, PhD
The PI3K-delta inhibitor umbralisib (TGR-1202) induced an objective response rate (ORR) of 37% in patients with relapsed/refractory lymphoma or chronic lymphocytic leukemia (CLL), according to phase I findings published in The Lancet Oncology.1

In the dose-escalation study, 62% of 90 patients experienced reduction in disease burden. The highest response rates occurred in patients with CLL (85%) and follicular lymphoma (53%).

Investigators also found that grade 3/4 immune mediated adverse events (AEs) commonly associated with other PI3K delta inhibitors were limited—3 patients (<3%) experienced transaminitis and 2 (<2%) each experienced pneumonia and colitis.

“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3K delta and CK1 epsilon, as previously described in our Blood paper,” study investigator Owen A. O’Connor, MD, PhD, professor of medicine and experimental therapeutics and director of Lymphoid Malignancies at Columbia Presbyterian Medical Center, said in a press release. “The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3K delta inhibitors.”

The phase I trial, which was conducted at 7 clinics in the United States, included ninety adult patients with CLL (27%; n = 24), B-cell non-Hodgkin lymphoma (54%; n = 49), Hodgkin lymphoma (12%; n = 11), or other hematological malignancies (7%; n = 6). Patients were enrolled between January 2013 and January 2016. Seventy-three patients were included in the intent-to-treat population.

At the November 2016 data cutoff, 44 patients (49%) had received umbralisib for more than 6 cycles (168 days), and 23 (26%) had received treatment for more than 12 cycles (336 days). The median duration of treatment and follow-up was 4.7 cycles (IQR, 2.0-14.0) or 133 days (IQR, 55-335), with a mean of 9.6 cycles administered. The recommended phase II dose was determined to be 800 mg of a micronized formulation of umbralisib.

Of the 24 patients with CLL, 10 (42%) had high-risk cytogenetics, including 2 with a 17p deletion, 7 with an 11q deletion, and 1 with both. Seventeen (85%) of the 20 evaluable patients with CLL had an objective response. Ten (50%) had an objective response per 2008 IWCLL criteria, 7 (35%) had a partial response with lymphocytosis, and the remaining 3 (15%) had stable disease.

Of the 8 assessable patients with CLL who had high-risk cytogenetic features, 6 (75%) had a response, including 2 partial responses with lymphocytosis. Nine (53%) of 17 patients with follicular lymphoma (FL) had objective response including 2 (12%) who had a complete response; the remainder had a partial response. Four (31%) of 13 patients with diffuse large B-cell lymphoma (DLBCL) had an objective response and two (15%) further patients achieved stable disease.

In a posthoc exploratory analysis, tumor reductions in most patients with indolent lymphoma and CLL tended to improve over time. The mean duration of response was 13.4 months (95% CI, 7.7-19.1) in 16 patients in the CLL cohort, 6.4 months (95% CI, 4.5-17.3) in 4 patients in the DLBCL cohort, and 9.3 months (95% CI, 3.6-15.1) in 9 patients in the FL cohort.

All 90 patients were included in the safety analysis. The most common treatment-emergent AEs regardless of cause were diarrhea (43%), nausea (42%), and fatigue (31%).

The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%). Three (3%) cases of pneumonia, 2 (2%) cases of colitis, 1 (1%) case of febrile neutropenia, and 1 (1%) case of lung infection were considered serious AEs at least possibly related to umbralisib. One patient with colitis also developed febrile neutropenia.

In an accompanying editorial, Jacqueline Claudia Barrientos, MD, associate professor with the Karches Center for Oncology Research at The Feinstein Institute for Medical Research, wrote that PI3K inhibitors fell out of favor after idelalisib (Zydelig) was found to cause life threatening autoimmune complications and infections.2 However, preclinical data showing that umbralisib can induce cell death in lymphoma cells lines and the “modest activity” seen in this study may lead researchers to take another look at this class of drugs.

“Is it possible that the time has come for PI3Kδ signaling inhibition to come out of the shadows and become an attractive target again? The clinical activity and safety reported with umbralisib in this study is encouraging,” she wrote. “Ongoing combination trials might achieve the desirable fine balance of efficacy and safety without increased toxicities, but only time will tell whether the unique mechanism of dual inhibition of PI3Kδ and casein kinase-1ε can be used in a safe manner while preserving patients' quality of life.”

References

  1. Burris HA, Flinn IW, Patel MR, et al. 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 [published online February 20, 2018]. Lancet Oncol. doi: 10.1016/ S1470-2045(18)30082-2
  2. Barrientos JC. Can umbralisib bring PI3Kδ out of the shadows? [published online February 20, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30154-2.



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