TGR-1202 and Ublituximab Show Promise in CLL

Author(s):

As the targeted therapy era in chronic lymphocytic leukemia (CLL) continues to unfold, two next-generation agents are generating responses with improved safety profiles as single agents and in combination regimens

Howard A. “Skip” Burris III, MD

TGR-1202 is a PI3K-delta inhibitor administered in once-daily oral dosing while ublituximab (TG-1101) is a glycoengineered anti-CD20 monoclonal antibody, explained Burris during the hematologic malignancies session as the 2014 Chemotherapy Foundation Symposium opened Wednesday.

Notably, ublituximab will be evaluated in combination with ibrutinib (Imbruvica) in patients with previously treated high-risk CLL in a phase III trial expected to be launched this year. The trial aims to enroll approximately 330 patients who harbor 17p or 11q chromosomal deletions, or TP53 mutations.

The new regimens are being developed as part of an emerging therapeutic landscape in CLL in which it is “not unrealistic to talk about, if not a cure for patients, certainly [patients] living long enough to die of other causes and from natural means,” said Burris.

Burris specializes in early-phase clinical trials at the Sarah Cannon Research Institute in Nashville, Tennessee, where he is chief medical officer and executive director of the Drug Development Program. He was honored earlier this year with a Giants of Cancer Care™ award, a program that the Intellisphere Oncology Specialty Group launched to recognize oncology specialists who have made significant contributions to cancer care.

The structures of both TGR-1202 and ublituximab offer potential advantages, Burris noted.

He said TG-1202’s structure “contributes to a favorable pharmacokinetic profile which enables once-daily dosing and a differentiated safety profile” from other PI3K-delta inhibitors such as the recently approved idelalisib (Zydelig) and IPI-145 still in development. He said hepatic toxicities have been “noticeably absent,” and that there have not been colitis events.

Ublituximab binds to a unique epitope on the CD20 antigen and is glycoengineered for enhanced affinity for FcγRIIIa receptors, resulting in enhanced antibody-dependent cell-mediated cytotoxicity, said Burris.

“Both TGR-1202 and ublituximab have displayed single-agent activity in a variety of relapsed/refractory hematologic malignancies,” said Burris.

The favorable safety profile that each drug has demonstrated as monotherapy has also been evident when the two novel agents were combined in a phase I involving 21 patients with CLL, diffuse large B-cell lymphoma, Richter, and follicular lymphoma. Overall, 14 of 15 evaluable patients achieved stable disease ≥12 weeks with manageable neutropenia and infusion-related reactions as thre most frequently reported adverse events, according to results presented at the Pan Pacific Lymphoma Conference held in Hawaii in July (Lunning et al).

In his symposium abstract, Burris presented findings for evaluable patients with CLL who received the drugs across all studies, which he said constituted the largest patient population whose experiences could be analyzed.

In the most advanced regimen under study, investigators will seek to determine whether the addition of ublituximab improves upon outcomes delivered by ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor that the FDA approved this year in combination with chlorambucil for patients with previously untreated CLL and as monotherapy for patients with 17p deletions.

In a phase II trial, all of the 20 patients who were among the first group enrolled in the study responded to the combination, said Burris. Findings were presented at the 19th Congress European Hematology Association held in Italy in May (Sharman et al).

The phase III study involving ublituximab and ibrutinib was designed under a special protocol agreement (SPA) between the FDA and TG Therapeutics, which is developing both TGR-1202 and ublituximab. Burris said patients will be stratified by prior lines of therapy and then randomized to receive either ublituximab and ibrutinib in combination or ibrutinib alone.

The overall response rates for the first 200 patients to be treated will be analyzed as the basis for an accelerated approval for ublituximab. Progression-free survival will be evaluated for all 330 participants in the trial as the primary endpoint for a full approval, said Burris.

"It’s certainly a novel way to approach this,” Burris said.

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