Study Demonstrates Potential for New CLL Combination

When treating patients with previously-treated high-risk chronic lymphocytic leukemia (CLL), adding ublituximab (TG-1101) to Imbruvica (ibrutinib) resulted in significantly improved objective response rates (ORR) compared to Imbruvica alone, according to findings from the phase 2 GENUINE trial announced by TG Therapeutics, the company developing the therapy.

In the open-label study, the ORR with ublituximab plus Imbruvica was 80 percent compared with 47 percent for Imbruvica alone. The combination was well tolerated with no new safety concerns, although data were not yet released for safety. Full findings from the trial are being prepared for presentation at an upcoming medical meeting. Additionally, TG Therapeutics plans to submit the data to the Food and Drug Administration (FDA) for a potential approval.

"Ibrutinib has been a great addition to our CLL armamentarium, however we have long believed that ibrutinib alone may not be enough, particularly for patients with high-risk disease," lead investigator Jeffrey Sharman, M.D., Medical Director for Hematology Research for the US Oncology Network, said in a statement. "This study demonstrates that the addition of ublituximab, can significantly enhance the response rates without compromising safety."

In the GENUINE study, 126 patients were randomized to receive Imbruvica alone (58 patients) or in combination with intravenous ublituximab (59 patients). Imbruvica was given once daily at 420 mg. Ublituximab was administered at 900 mg on days one, eight and 15 during the first cycle and then on day one alone for cycles two through six. Those who did not progress after six cycles continued to receive maintenance ublituximab once every three months at 900 mg. All patients in the trial had received at least one prior therapy. High risk was defined as having a 17p deletion, 11q deletion and/or p53 mutation.

In addition to improving ORR, the combination of Imbruvica and ublituximab also improved several secondary endpoints compared with single-agent Imbruvica. Overall, the combination improved radiographic complete response, progression-free survival, and time to response compared with Imbruvica alone, according to the statement.

"We believe the results observed in the combination arm are extremely compelling and the regimen has the potential to become the standard of care for treating patients with high risk CLL that have progressed from other therapies," Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, said in a statement. "We believe that using combination therapy to accelerate and deepen response in poor prognosis high risk CLL is critically important for patient outcomes and we look forward to sharing these data with the FDA in the coming months to discuss filing for accelerated approval."

The company noted that safety and efficacy findings in the phase 3 GENUINE study were similar to a prior phase 2 investigation. In this trial, the combination demonstrated an ORR of 88 percent at six months in 41 evaluable patients with CLL. In 20 patients with high-risk CLL, the ORR was 95 percent, with a 15 percent minimal residual disease-negativity rate.

The median time to response was eight weeks. In the full population, the median nodal reduction was 62 percent at week eight and 77 percent at week 20. In those with high-risk CLL, the median nodal reduction was 64 percent at week 8 and 85 percent at week 20.

The most common all-grade adverse events (AEs) with the combination were infusion-related reactions (53 percent), diarrhea (40 percent), fatigue (33 percent), cough (27 percent), rash (27 percent) and nausea (24 percent). The most common grade 3/4 AEs were anemia (11 percent), neutropenia (11 percent), thrombocytopenia (7 percent), infusion-related reactions (7 percent), diarrhea (4 percent) and arthralgia (2 percent).

"We believe that the rapid responses seen in our phase 2 study with ublituximab plus ibrutinib are validated here in our phase 3 GENUINE study and are important markers of improved overall efficacy and patient outcomes," said Sharman. "I look forward to the presentation of the results at an upcoming medical meeting."

Several studies are currently assessing ublituximab for patients with hematologic malignancies. The agent is being explored in combination with TGR-1202, a PI3K-delta inhibitor, in comparison with Gazyva (obinutuzumab) and chlorambucil for patients with untreated or relapsed CLL (NCT02612311). Ublituximab and TGR-1202 are also being looked at with or without Imbruvica or bendamustine for patients with B-cell malignancies (NCT02006485).