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Novel chemotherapy-free regimen shows promise in relapsed, refractory CLL

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ORLANDO — A chemotherapy-free, triplet combination regimen of umbralisib, ublituximab and venetoclax was well-tolerated and achieved high rates of undetectable minimal residual disease after 12 cycles of therapy among patients with relapsed or refractory chronic lymphocytic leukemia, according to preliminary results of a phase 1/2 trial presented at ASH Annual Meeting and Exposition.

“Despite the effectiveness of novel agents in treating CLL, single-agent use requires prolonged administration, which can lead to drug resistance, toxicity and considerable cost over time,” Paul M. Barr, MD, associate professor and medical director of the Cancer Center Clinical Trials Office at the University of Rochester, and colleagues wrote. “Combinations may provide deeper prolonged remissions using defined treatment durations.”

Umbralisib (TGR-1202, TG Therapeutics) is a novel PI3 kinase (PI3K) inhibitor and ublituximab (TG-1101, TG Therapeutics) is a glycoengineered anti-CD20 monoclonal antibody designed to enhance antibody-dependent cellular toxicity, according to the researchers.

“Phase 1 results of the ‘U2’ regimen, as it is termed, were recently published and showed that the combination is well-tolerated and effective,” Barr said during the presentation.

The researchers launched a phase 1/2 trial to evaluate the impact of combining the U2 regimen with the BCL2 inhibitor venetoclax (Venclexta; AbbVie, Genentech) among patients with relapsed or refractory CLL. They hypothesized that the regimen could prevent drug resistance and reduce the risk for tumor lysis syndrome (TLS) that is associated with venetoclax ramp-up.

“We also hypothesized that the three-drug regimen would achieve [minimal residual disease] negativity using a relatively short duration of treatment,” Barr said.

The researchers assigned patients to three cycles of induction/debulking therapy with ublituximab (900 mg) and escalating doses of umbralisib (600 mg and 800 mg). The patients then received an additional nine cycles of treatment with venetoclax (5-week ramp-up to 400 mg) and umbralisib. At the end of the 12-month treatment period, all patients underwent a full response assessment, including minimal residual disease (MRD) testing. Patients with undetectable MRD in peripheral blood and bone marrow could stop all therapies. Those with detectable MRD could continue treatment with umbralisib as a single agent.

Twenty-seven patients (median age, 63 years) were enrolled in the trial at the time of data presentation. Patients had received a median one prior regimen before starting the study treatment. About one-quarter of patients were refractory to their last therapy, and about half had received a Bruton tyrosine kinase inhibitor.

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During the trial, two patients discontinued treatment due to a grade 3 rash and grade 3 diarrhea, respectively. Nine patients completed all 12 cycles of treatment.

The 67% rate of infusion reactions was higher than expected, Barr said. Other adverse events included leukopenia (56%), creatine increase (48%), thrombocytopenia (48%), anemia (44%), nausea (37%), aspartate aminotransferase increase (37%), diarrhea (33%), alkaline phosphatase increase (30%), fatigue (30%), alanine aminotransferase increase (26%), hypocalcemia (26%), rash (26%) and hyperkalemia (19%). No TLS events occurred.

“Three cycles of U2 induction did seem to effectively reduce the venetoclax-tumor lysis risk,” Barr said. “At baseline, there were three patients at high risk and 12 at medium risk for tumor lysis. The majority were converted to low risk after the three-cycle induction, with no high-risk patients remaining.”

The overall response rates were 87% after the third cycle of treatment and 100% after the seventh and 12th cycles of treatment. After cycle 12, 44% of patients had a complete response, all patients achieved MRD negativity in the blood and 79% achieved MRD negativity in the bone marrow.

To date, no patients experienced disease progression, “albeit with a relatively short follow-up of only 6 months,” Barr said.

“In conclusion, umbralisib, ublituximab and venetoclax appears well-tolerated,” he continued. “The three-cycle U2 induction effectively mitigates the TLS risk. Myelosuppression and GI effects were very manageable, with a low rate of discontinuation, so far. There is early evidence of MRD negativity. All patients will continue to be followed for MRD in the peripheral blood every 6 months.”

Enrollment of the phase 2 trial is ongoing. The trial has been expanded to include patients with Richter’s transformation and mantle cell lymphoma. In addition, a larger phase 2 study, known as ULTRA-V, has been initiated “to further explore the regimen and potentially seek regulatory approval,” Barr said. – by Stephanie Viguers

Reference:

Barr PM, et a. Abstract 360. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.

Disclosures: Barr reports a consultant role with AbbVie, AstraZeneca, Celgene, Genentech, Gilead, Janssen, Merck, Pharmacyclics LCC, Seattle Genetics, TG Therapeutics and Verastem, and research funding from AstraZeneca, Pharmacyclics LLC and TG Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.