Chemotherapy-free triplet therapy appears safe, effective for B-cell malignancies

CHICAGO — A chemotherapy-free triplet composed of ublituximab, TGR-1202 and ibrutinib demonstrated significant early activity and tolerability in patients with heavily pre-treated or high-risk B-cell malignancies, according to study results presented at the ASCO Annual Meeting.

“Combinations of unique and novel targeted agents represent the best hopes for patients with relapsed B-cell malignancies,” Nathan H. Fowler, MD, of the department of lymphoma and melanoma at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “Based on the proven single agent activity of Bruton’s tyrosine kinase inhibitors, phosphoinositide-3 inhibitors and next generation monoclonal antibodies in lymphoma and leukemia — as well as the potential for biologic synergy — we decided to design and test a chemotherapy-free triplet regimen.”

Few studies have safely combined the multiple novel targeted agents under development for the treatment of B-cell malignancies, according to study background.

Fowler and colleagues sought to evaluate the safety and efficacy of the triplet combination of ublituximab, the phosphoinositide-3 inhibitor TGR-1202 (TG Therapeutics) and the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica, Pharmacyclics).

The analysis included 16 patients (median age, 63 years; range, 51-85) with relapsed or refractory chronic lymphoblastic leukemia or B-cell non-Hodgkin’s lymphoma with poor ECOG scores (≤ 2) and unlimited prior treatments. Diseases represented in the patient population included follicular lymphoma (n = 4), CLL (n = 4), marginal zone lymphoma (n = 1), mantle cell lymphoma (n = 1) and Richter’s diffuse large B-cell lymphoma (n = 1).

The researchers assigned patients a dose-escalating combination of ublituximab (900 mg on days 1, 8 and 15 of cycles 1 and 2 and day 1 of cycles 4, 6, 9 and 12), escalating TGR-1202 (400 mg, 600 mg, 800 mg and 1,200 mg) and ibrutinib (420 mg for patients with CLL and 560 mg for patients with non-Hodgkin’s lymphoma).

The researchers separately evaluated the safety and efficacy of the combination based on disease cohort.

Safety served as the primary endpoint.

At the time of reporting, the researchers reported no dose-limiting toxicities up to the currently evaluated dose of 800 mg for TG-1202. The most commonly reported adverse events included diarrhea (30%), constipation (30%), fatigue (30%), day 1 infusion-related reactions (20%,) and neutropenia (20%). All of these adverse events were grade 1 or grade 2 with the exception of one grade 3 to grade 4 neutropenia, and one grade 3 leukopenia.

Researchers evaluated efficacy in thirteen patients. The overall response rate (ORR) was 69%, with all but three patients — two with large cell lymphoma and one with Richter’s DLBCL — responding. Researchers observed one complete response and five partial responses at week 8.

“Encouraging early results suggest the triplet combination has significant activity in patients who have failed to improve on traditional chemotherapy,” Fowler said. “We are expanding the study to further explore the potential for this novel approach in various B-cell cancers.” – by Cameron Kelsall

Reference:

Fowler NH, et al. Abstract 8501. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

For more information:

Nathan H. Fowler, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; e-mail: nfowler@mdanderson.org.

Disclosure: Fowler reports research funding from and a consultant role with Celgene, Pharmacyclics, Roche and TG Therapeutics. Please see the abstract for a list of all other researchers’ relevant financial disclosures.