Umbralisib/Ublituximab Plus Venetoclax Triplet Moves Into Phase 3 Testing as Phase 2 Trial Completes Accrual in CLL

Patient enrollment has commenced for the randomized phase 3 ULTRA-V trial, which will evaluate the efficacy of a time-limited combination of umbralisib (Ukoniq) plus ublituximab and venetoclax (Venclexta) vs continuous umbralisib/ublituximab in patients with newly diagnosed or relapsed/refractory chronic lymphocytic leukemia (CLL).¹

“While recent approvals provide excellent treatment options for patients, disease progression and treatment tolerability still remain problematic for many patients. Our belief is that time-limited treatment regimens, such as [umbralisib/ublituximab] plus venetoclax, have the potential to produce meaningful responses without the need to expose patients to continuous therapy and related toxicities,” said Richard R. Furman, MD, director of the CLL Research Center at Weill Cornell Medicine and study chair for the phase 2 and 3 ULTRA-V studies.

The open-label, multicenter, phase 3 study will independently randomize 2 cohorts of patients with newly diagnosed CLL and previously treated CLL to the time-limited triplet regimen vs the continuous doublet regimen.

Progression-free survival will serve as the primary end point of the phase 3 study.

In addition, the ongoing, single-arm phase 2 ULTRA-V trial (NCT03801525), which is evaluating the same triplet regimen in patients with CLL, completed patient enrollment with approximately 165 participants with newly diagnosed or relapsed/refractory CLL.

Notably, some of the patients with relapsed/refractory disease received prior BTK inhibitors.

The primary end point of the phase 2 study is overall response rate (ORR). The incidence of treatment-related adverse effects (AEs) serves as the secondary end point.²

Eligible patients for the phase 2 study had to have CLL that required treatment and adequate organ system function. Patients who underwent autologous hematologic stem cell transplant (HSCT) within 6 months of the study entry or allogeneic HSCT at any time point were not eligible to enroll.

Patients on the triplet regimen will receive 900 mg of weekly intravenous ublituximab in a split dosing regimen and then on day 1 of cycles 2 through 6 plus daily, oral umbralisib, plus oral venetoclax starting at cycle 4 in a ramp-up dosing schedule until reaching 400 mg to be continued from cycle 5 to 24.³

The phase 2 and 3 trials were initiated based on positive results from a phase 1/2 trial (NCT03379051), which demonstrated an ORR of 76% after umbralisib/ublituximab debulking, 100% after cycle 7 of umbralisib/ublituximab plus venetoclax, and 100% after cycle 12 of the triplet.⁴ In 19 patients who completed 12 cycles of therapy with umbralisib/ublituximab plus venetoclax, the complete response rate was 42%.

Moreover, undetectable minimal residual disease (uMRD) in the peripheral blood was observed in 95% of patients (n = 18), and uMRD in the bone marrow was observed in 68% of patients (n = 13).

Regarding safety, the most common all-grade AEs included infusion-related reactions (IRRs; 63%), anemia (55%), thrombocytopenia (53%), neutropenia (53%), leukopenia (50%), creatinine increase (50%), fatigue (45%), diarrhea (43%), nausea (38%), and aspartate aminotransferase increase (30%). Grade 3/4 AEs occurring in 5% of patients or more included neutropenia (23%), leukopenia (13%), and IRRs (8%).

Two patients developed PI3K inhibitor–associated AEs, which included 1 case each of grade 3 colitis and grade 3 diarrhea.

Notably, no instances of tumor lysis syndrome (TLS) were reported during venetoclax administration. Moreover, patients who were at a high or moderate risk for TLS at baseline experienced a 79% reduction in TLS risk after 3 cycles of umbralisib/ublituximab debulking.

Three patients discontinued any study drug because of toxicity and 1 patient, who experienced grade 3 diarrhea, discontinued all 3 agents.

“We are excited to launch this pivotal phase 3 study based on the promising phase 1 clinical results reported to date on the triplet combination of [umbralisib], ublituximab and venetoclax in patients with CLL,” concluded Furman, who is also an attending physician and associate attending physician at NewYork-Presbyterian Hospital, as well as a professor of medicine and the Morton Coleman, MD, Distinguished Professor of Medicine at Weill Cornell Medical College of Cornell University.1

References

1. TG Therapeutics announces launch of the ULTRA-V phase 3 trial evaluating the triple combination of UKONIQ™ (umbralisib), ublituximab, and venetoclax. News release. TG Therapeutics. Published April 21, 2021. https://bit.ly/3vaidhk.
2. Study to assess the efficacy and safety of ublituximab in combination with umbralisib and venetoclax compared to ublituximab in combination with umbralisib in subjects with CLL (ULTRA-V) (ULTRA-V). ClinicalTrials.gov. Updated April 23, 2021. Accessed April 25, 2021. https://clinicaltrials.gov/ct2/show/NCT03801525.
3. Barr PM, Ma S, Zent CS, et al. A phase 1/2 study of umbralisib, ublituximab, and venetoclax (U2-Ven) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood. 2020;136(suppl 1):41-42. doi:10.1182/blood-2020-134818