FDA Grants Ublituximab/Umbralisib Combo Fast Track Status in CLL

The FDA has granted a fast track designation to the investigational CD20-directed monoclonal antibody ublituximab in combination with the PI3K-delta inhibitor umbralisib for the treatment of adult patients with chronic lymphocytic leukemia.

The FDA has granted a fast track designation to the investigational CD20-directed monoclonal antibody ublituximab in combination with the PI3K-delta inhibitor umbralisib (U2 regimen) for the treatment of adult patients with chronic lymphocytic leukemia (CLL).1

Positive topline results of the combination were unveiled in May 2020 from the phase 3 UNITY-CLL trial, in which the doublet improved progression-free survival (PFS) compared with obinutuzumab (Gazyva) plus chlorambucil in patients with previously untreated and relapsed/refractory disease.2 The study is being conducted under a Special Protocol Assessment agreement with the FDA.

An independent review panel determined that the chemotherapy-free U2 combination induced a statistically significant improvement in PFS (P < .0001), and the panel recommended that the trial be stopped early.

"We are extremely pleased to have received fast track designation for the ublituximab plus umbralisib regimen, or the U2 combination, to treat adult patients with CLL. The application for Fast Track was based on data from the UNITY-CLL phase 3 study that we announced earlier this year had met its primary endpoint of progression free survival,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics, the developer of both agents.

In the phase 3 UNITY-CLL trial, patients with both treatment-naïve and relapsed/refractory CLL were initially randomized into 1 of 4 treatment arms: single-agent ublituximab; single-agent umbralisib; U2; or obinutuzumab plus chlorambucil. The trial design did allow for discontinuation of the 2 monotherapy arms following a positive assessment of the U2 combination. Randomization, at that point, continued with the U2 and obinutuzumab/chlorambucil arms only.

Overall, the trial enrolled 420 patients across these 2 arms, which comprised approximately 60% treatment-naïve patients and 40% of relapsed/refractory patients. The primary endpoint is PFS and, if positive, will be used to support the submission for full approval of the U2 combination in this patient population.

Previously, a number of doublet and triplet combinations including umbralisib and/or ublituximab have shown intriguing results in CLL. For example, the triplet regimen of pembrolizumab (Keytruda) plus umbralisib/ublituximab induced a 90% objective response rate (ORR) in patients with relapsed/refractory disease.3 Nine of 10 patients with CLL receiving the triplet achieved a response, including 1 complete response (CR) and 8 partial responses (PRs), according to data from a phase 1/2 study presented at the 2018 ASH Annual Meeting.

Furthermore, the triplet of umbralisib, ublituximab, and venetoclax (Venclexta) induced a CR rate of 44% as a treatment for patients with relapsed/refractory chronic CLL in a phase 1/2 dose-escalation study.4 At the end of 12 cycles of treatment with the regimen, the ORR was 100%, which included the CR rate of 44%. In an assessment of peripheral blood, all patients were negative for minimal residual disease (MRD). In the bone marrow, 78% were MRD-negative (< .01%) and 22% were MRD intermediate (.01% to 1.0%). At a median follow-up of 6.4 months (range, 0.7 to 19.0+), no patients had progressed.

In long-term data from the phase 3 GENUINE study, the combination of ublituximab and ibrutinib (Imbruvica) improved PFS, as determined by an independent review committee, versus single-agent ibrutinib in patients with relapsed/refractory high-risk CLL.5 Results showed that the ORR was 78%, which included a CR rate of 7%, compared with a 45% ORR in the single-agent ibrutinib arm where there were no CRs. Additionally, 19% of patients in the ublituximab arm were MRD negative versus 2% of patients on ibrutinib alone. Overall, 66% of patients had a >75% decrease in lymph node size with ublituximab plus ibrutinib compared with 52% for ibrutinib alone.

“This designation holds several important advantages to potentially expedite the development and regulatory review of U2 and underscores the significant unmet medical need that still exists for patients with CLL,” Weiss concluded. “We look forward to presenting data from the UNITY-CLL phase 3 trial later this year, which we plan to use as the basis of a U2 regulatory submission for CLL.”


  1. TG Therapeutics announces fast track designation granted by the FDA to ublituximab in combination with umbralisib for the treatment of adult patients with chronic lymphocytic leukemia. News release. TG Therapeutics. October 21, 2020. Accessed October 21, 2020. https://bit.ly/3oczEey
  2. TG Therapeutics announces positive topline results from the UNITY-CLL phase 3 study evaluating the combination of umbralisib and ublituximab (U2) for the treatment of patients with chronic lymphocytic leukemia. May 5, 2020. Accessed May 5, 2020. https://bit.ly/3fq9Ire
  3. Mato AR, Svoboda J, Luning Prak ET, et al. Phase I/II study of umbralisib (TGR-1202) in combination with ublituximab (TG-1101) and pembrolizumab in patients with relapsed/refractory CLL and Richter’s transformation. Presented at: 2018 ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, CA. Abstract 297.
  4. Venetoclax (U2-Ven) in Patients with Relapsed/Refractory CLL. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 360.
  5. Sharman JP, Brander DM, Mato AR, et al. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: results of the GENUINE phase 3 study. J Clin Oncol. 2017;35 (suppl; abstr 7504). doi:10.1200/JCO.2017.35.15_suppl.7504