TG-1701 (TG Therapeutics) is an investigational, once-daily, selective, convalent, oral Bruton tyrosine kinase inhibitor. Prior research has shown that inhibition of Bruton tyrosine kinase is superior to standard chemoimmunotherapy in the management of treatment-naïve and relapsed/refractory chronic lymphocytic leukemia, as is the “U2” combination of the novel glycoengineered anti-CD20 monoclonal antibody ublituximab plus the once-daily PI3K-delta and CK1-epsilon inhibitor umbralisib. An international team of researchers conducted a study to assess the dose escalation of TG-1701 monotherapy and TG-1701 as triple therapy when administered with U2.

Dose Escalation of TG-1701

The study—initially meant to evaluate the dose escalation of once-daily, oral TG-1701 continuously administered in 28-day cycles at 100, 200, 300, and 400 mg—enrolled patients with relapsed/refractory chronic lymphocytic leukemia and lymphoma. Lead by Dr. Chan Cheah, the lymphoma lead and Fellowship Program Director at Sir Charles Gairdner Hospital and Founder of Blood Cancer Research WA at the University of Western Australia, the study team implemented a parallel dose escalation arm of TG-1701 plus U2 after they characterized the safety profile of TG-1701 monotherapy.

Select dose levels of TG-1701 monotherapy were expanded in patients with chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia, with all patients treated until disease progression. As of June 4, 2021, 125 patients had been treated with TG-1701, including 25 in the monotherapy dose escalation arm, 61 in the 200 mg disease-specific cohorts (20 with chronic lymphocytic leukemia [5 treatment-naïve], 21 with mantle cell lymphoma [4 treatment-naïve], 20 with Waldenström’s macroglobulinemia [8 treatment-naïve]), 20 in the 300 mg chronic lymphocytic leukemia cohort (4 treatment-naïve), and 19 in the TG-1701 plus U2 dose escalation arm. Participants had a median of one prior therapy, with a range of one to 10, all were Bruton tyrosine kinase inhibitor-naïve, and all were evaluable for safety. For the ongoing study, “the primary objectives are to characterize the safety profile and define the recommended Ph 2 doses for the drugs alone and in combination,” write Dr. Cheah and colleagues.

TG-1701 Well Tolerated With Good Response Rate

The researchers found TG-1701 monotherapy to be well tolerated, with a maximum tolerated dose not reached up to 400 mg daily, “demonstrating near 100% saturation of the [Bruton tyrosine kinase] at all dose levels studied,” according to the study team.

Overall response rates in the 200 mg daily monotherapy expansion cohorts during a median follow-up of 12.2 months were 95% (19/20) among patients with chronic lymphocytic leukemia, 65% (13/20) among those with mantle cell lymphoma, and 95% (19/20) among those with Waldenström’s macroglobulinemia. At a median follow-up of 8.6 months, the overall response rate in the 300 mg monotherapy chronic lymphocytic leukemia cohort was 100%. TG-1701 plus U2 dose escalation (using TG-1701 100 mg to 300 mg daily) resulted in a 79% overall response rate at a median follow-up of 15.6 months, with a 21% complete response rate across patients with Waldenström’s macroglobulinemia, chronic lymphocytic leukemia, marginal zone lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma.

Low Adverse Event Rates

Among patients treated with TG-1701 200 mg and 300 mg daily (n=81), adverse events of special interest included Grade 3 hypertension (4.9%) and atrial fibrillation (1.2%), with no observed cases of major bleeding. Grade 3 adverse events that occurred in at least 10% of patients treated with TG-1701 plus U2 included diarrhea (11%), neutropenia (11%), alanine aminotransferase increase (16%), and aspartate aminotransferase increase (16%). Neutropenia (11%) was the only Grade 4 adverse event that occurred in at least 10% of patients treated with TG-1701 plus U2. Treatment-emergent adverse events leading to treatment discontinuation occurred in just 1.6% of patients and included atrial fibrillation and COVID-19.

“We are pleased to see that with additional patients and longer follow-up, TG-1701, our BTK inhibitor, continues to show encouraging clinical activity paired with what appears to be a tolerable safety profile, especially in the triple combination with U2,” said TG Therapeutics Executive Chairman and CEO Michale S. Weiss. “It is also exciting to see some early complete responses in patients treated with the triple therapy. We look forward to continuing to enroll on this trial and presenting additional data.”