Novel Triplet Shows Early Promise for Pretreated CLL

Paul M. Barr, MD

The triplet of umbralisib, ublituximab, and venetoclax (Venclexta) induced a complete remission (CR) rate of 44% as a treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to findings from a phase I/II dose escalation study presented at the 2019 ASH Annual Meeting.

At the end of 12 cycles of treatment with the regimen, the objective response rate (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, 0.7-19.0+), no patients had progressed.

"There's early evidence of MRD-negativity, and all patients will continue follow up for MRD in the peripheral blood every 6 months," Paul M. Barr, MD, Wilmot Cancer Institute, University of Rochester, said during the presentation. "The study has a been expanded to explore the combination in Richter's transformation as well as mantle cell lymphoma. A large phase II study has been initiated, termed the ULTRA-V study, to further explore the regimen with the intention of gaining regulatory approval."

Umbralisib is a dual PI3K delta and CK1 epsilon inhibitor that has a unique structure and improved tolerability compared with other agents in the class, Barr said. Ublituximab is a glycoengineered CD20 inhibitor and venetoclax is a BCL2 inhibitor. The combination is backed by preclinical evidence showing synergistic cytotoxicity between inhibition of the B cell receptor and BCL2. Additionally, targeting PI3K could help prevent resistance to BCL2 inhibition.

At the time of the analysis, 27 patients were evaluable for safety and 23 were assessable for efficacy. The median age of patients was 63 years, and 81.4% had ECOG performance status of 1. The median creatinine clearance at baseline was 75 mL/min and the median number of prior regimens was 1 (range, 1-5). A quarter of patients were refractory to their immediate prior therapy (26%). Prior exposure to a BCL2 or PI3K inhibitors was allowed before study entry. Prior BTK inhibition was also permitted, with a 21-day washout period. Overall, 54% of patients were refractory to a BTK inhibitor. More than half of patients (52%) had at least 1 high-risk feature.

Ublituximab and umbralisib were administered together as induction in the first 3 cycles before the addition of venetoclax, to abate the risk of tumor lysis syndrome (TLS). Ublituximab was only administered during the 3-cycle induction period. Consolidation with venetoclax and umbralisib lasted from cycle 4 to cycle 12. Those testing positive for MRD after consolidation could continue to receive umbralisib monotherapy.

Ublituximab was infused at a fixed 900 mg dose on days 1/2, 8, and 15 of cycle 1 and then day 1 of the next 2 cycles. Daily umbralisib was escalated from 600 mg to 800 mg, with 3 patients receiving the 600 mg dose and 6 the 800 mg dose, which was recommended for phase II studies. An additional 18 patients were enrolled at the 800 mg dose in the phase II portion of the study. Venetoclax was administered at the standard 5-week ramp up dosing to 400 mg in the consolidation period.

Following induction therapy, there was a mean 61% reduction from baseline in lymph node size with an ORR of 87%. By cycle 7, the ORR was 100%. At the end of the consolidation period (cycle 12), mean lymph node size had declined by 87%. Absolute lymphocyte count, which was a mean of 48,000 per μL at baseline, declined to 3400 per μL by the end of cycle 6.

"Although it's a relatively small cohort with short follow up, there doesn't seem to be any differences in treatment effect duration for those treated with prior BTK inhibitors," said Barr. "No patients have progressed with CLL, although it is a relatively short follow up of only 6 months."

During the induction phase, 1 patient discontinued the study to address grade 3 rash. Additionally, in the consolidation portion, 1 patient discontinued due to grade 3 diarrhea. There was 1 dose-limiting toxicity seen at the 800 mg dose of umbralisib, namely a lower gastrointestinal (GI) bleed that resolved in 3 days. The maximum tolerated dose was not reached, and dose modifications were relatively infrequent.

There were no cases of clinical or laboratory TLS and no patients developed grade 3/4 liver function test elevations. The most common all-cause grade 3/4 adverse events (AEs) were neutropenia (19%), leukopenia (15%), infusion reaction (7%), deep vein thrombosis (7%), anemia (4%), diarrhea (4%), rash (4%), lower GI bleed (4%), supra ventricular tachycardia (4%), anxiety (4%), hypophosphatemia (4%), and dyspnea (4%).

"Umbralisib, ublituximab, and venetoclax appears to be well tolerated at the phase II dose," said Barr. "The 3-cycle induction effectively mitigates TLS risk. Myelosuppression and GI effects were very manageable, with low risk of discontinuation so far."

Findings from the study will continue to mature, with a 12-month analysis planned. Additionally, the phase II portion of the study continues to enroll participants, with a recruitment goal of 30 (NCT03379051). The ULTRA-V study plans to enroll 90 patients with treatment-naive and relapsed/refractory CLL (NCT03801525).

Venetoclax (U2-Ven) in Patients with Relapsed/Refractory CLL. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 360.

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