FDA Grants Special Protocol Assessment to Phase III Ublituximab/Ibrutinib Study

Michael S. Weiss

TG Therapeutics has reached an agreement with the FDA regarding a Special Protocol Assessment (SPA) for a phase III clinical trial exploring ublituximab (TG-1101) in combination with ibrutinib (Imbruvica) for the treatment of patients with chronic lymphocytic leukemia (CLL), the company announced last week.

Ublituximab, a chimeric recombinant glycoengineered monoclonal antibody directed against CD20, is being developed as a treatment for patients with B-cell proliferative disorders, including non-Hodgkin's lymphoma (NHL) and CLL. As per the SPA agreement, overall response rate (ORR) data will be used from the phase III trial as the basis for submission of a Biologics License Application (BLA) for accelerated approval for ublituximab. All patients will then be followed for PFS assessment, which is designed to support full approval, according to a statement from the company.

"The TG-1101 SPA agreement is a major milestone for us as it represents the first clearly defined development and regulatory pathway for the approval of TG-1101 for the treatment of CLL,” Michael S. Weiss, executive chairman and interim chief executive officer of TG Therapeutics, said in a statement. “As we've mentioned previously, reaching agreement with the FDA on this combination trial with ORR as a primary endpoint for accelerated approval was our number one priority.”

The randomized controlled trial is planned to enroll approximately 330 patients, who will receive ublituximab plus ibrutinib or ibrutinib alone. The first assessment of the study is planned once ORR data is available for two-thirds of the enrolled patients. Full details of the phase III clinical trial will be released at the launch of the study, which is expected to occur before the end of the year, according to a statement from the company.

The SPA agreement comes after promising results from an ongoing phase II trial (UTX-IB-104) assessing the efficacy and safety of the combination were presented at the 19th Annual European Hematology Association (EHA) meeting in June.

In this trial, 28 patients with relapsed and/or refractory CLL or MCL were treated with ublituximab at doses of 600 mg or 900 mg in combination with ibrutinib at an oral daily dose of 420 mg for patients with CLL and 560 mg for patients with MCL.

The ORR at the first planned efficacy assessment for the 10 evaluable patients was 90%. In the CLL arm, 86% (6/7) achieved a partial response (PR), with the remaining one patient achieving a 40% nodal reduction coupled with a >50% reduction in absolute lymphocyte count (ALC). All of the MCL patients (3/3) achieved a response (1 CR and 2 PRs).

The study indicated that the addition of ublituximab mitigated ibrutinib-related lymphocytosis in patients with CLL, with a median 80% reduction in ALC by month 4 following initiation of combination therapy. At the time of the data announcement, no patients had progressed while on the combination, with patients on study for upwards of 5 months.

The combination of ublituximab and ibrutinib was well tolerated, with day 1 infusion related reactions (IRR) being the most frequently reported adverse event for ublituximab. All but one IRR were grade 1 or 2 in severity and were manageable without dose reductions. Ibrutinib-related adverse events included diarrhea and rash with one patient discontinuing treatment due to ibrutinib-related diarrhea.

TG Therapeutics has since closed the study and will report on the safety and efficacy findings of over 30 CLL patients at the Annual Meeting of the American Society of Hematology (ASH) this December.

"We have been very pleased with the safety and activity profile of the combination seen thus far in our phase I/II trial, and are excited to lead this important clinical trial,” Jeff Sharman, MD, medical director of Hematology Research for the US Oncology Network, and lead investigator on the phase II trial, said in a statement. “Combining a glycoengineered anti-CD20 monoclonal antibody with ibrutinib has the potential to materially increase the number of patients benefitting from treatment with ibrutinib therapy.”