Promising Clinical Activity Seen in Single Agent and Combination TG-1701 in CLL and Other B-Cell Malignancies

Encouraging clinical and pharmacodynamic activity was seen at all dose levels in patients with B-cell malignancies who received TG-1701, according to updated results from a phase 1/2 trial (NCT03671590) that were presented virtually during the 2021 ASCO Annual Meeting.¹

The maximum-tolerated dose of the BTK inhibitor was not achieved in patients who received TG-1701 monotherapy up to a dose of 400 mg daily (QD). The efficacy dose-escalation cohort, which administered 100 mg-400 mg of single-agent TG-1701 QD, reported an overall-response rate (ORR) of 57% after a median follow up of 20.3 months, while the disease-specific monotherapy cohort, which administered a 200 mg dose of the agent, yielded an ORR of 95% after a median follow up of 12.2 months in patients with chronic lymphocytic leukemia (CLL), 65% in patients with mantle cell lymphoma (MCL), and 95% in patients with Waldenström macroglobulinemia.

In the CLL cohort, a single-agent 300 mg dose yielded an ORR was 100% at a median follow up of 8.6 months. Additionally, a dose-escalation cohort that combined 100 mg-300 mg of TG-1701 with ublituximab (TGTX-1101) and umbralisib (Ukoniq) QD achieved an ORR of 79% at a median follow up of 15.6 months across multiple B-cell malignancies, with a complete response (CR) rate was 21%.

“The combination TG-1701 with ublituximab/umbralisib has been well-tolerated, and dose escalation continues,” lead study author Chan Cheah, MD, a clinical professor at the University of Western Australia Medical School , as well as a consultant hematologist at Sir Charles Gairdner Hospital, Pathwest Laboratory Medicine WA, Linear Clinical Research, and Hollywood Private Hospital, said during an oral presentation on the data. “The combination regimen is associated with encouraging clinical activity, including early complete responses. This study continues enrollment, and future registration trials are being planned.”

While patients with CLL and other B-cell malignancies have benefitted from treatment with BTK inhibitor monotherapies, CRs and deep remissions remain rare. TG-1701 is a covalently bound BTK inhibitor that has demonstrated superior selectivity vs other agents, such as ibrutinib (Imbruvica). Additionally, in vitro and in vivo data have demonstrated increased sensitivity to inhibition when combined with ublituximab/umbralisib in BTK-resistant xenograft models.^2,3

In the phase 1/2 dose-escalation trial, which included disease-specific cohorts of patients with CLL, MCL, and Waldenström macroglobulinemia, the primary objective was to examine the safety and efficacy of TG-1701 alone and in combination with ublituximab/umbralisib. Additionally, investigators sought to establish the recommended phase 2 dose for the monotherapy and combination regimen, as well as determine the pharmacokinetics, preliminary tumor activity, and BTK occupancy of the agent.

The trial enrolled patients who were relapsed or refractory to prior standard treatment and had histologically confirmed CLL or B-cell lymphoma warranting systemic treatment. The disease-specific study cohorts allowed treatment-naïve patients to enroll if they were not suitable for standard front-line chemoimmunotherapy. Adequate organ function was also required. Additionally, patients who had received prior treatment with a BTK inhibitor, or who had other severe or uncontrolled illness, were not able to enroll on the study. Patients receiving concomitant warfarin (Jantoven) therapy were also excluded from the trial, although other anticoagulants were allowed.

The dose-escalation portion of the trial included a TG-1701 monotherapy cohort and a TG-1701 plus ublituximab/umbralisib combination cohort. After the optimal dose had been determined, the trial then moved on to focus on the disease-specific cohorts, which examined both the single-agent and combination regimens

Oral TG-1701 was continuously administered QD in 28-day cycles. Additionally, intra-patient dose escalation were permitted in the monotherapy arms. In the combination arm, an escalating dose of TG-1701 was administered QD, plus an oral dose of umbralisib at 800 mg or 600 mg QD and an intravenous dose of ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6 and on day 1 of every 3 cycles thereafter.

In the dose-escalation monotherapy cohort, patients received TG-1701 at 100 mg QD (n = 3), 200 mg QD (n = 9; CLL, n = 20; MCL, n = 21; Waldenström macroglobulinemia n = 21), 300 mg QD (n = 3; CLL, n = 20), and 400 mg QD (n = 10).

In the dose-escalation combination cohort, patients received TG-1701 at 100 mg QD (n = 7) and 200 mg QD (n = 6) plus ublituximab/umbralisib. Additionally, patients in the cohort who received TG-1701 at 300 mg QD (n = 6), also received umbralisib at the 600 mg QD dose, plus ublituximab at the designated trial dose.

Among the patients who enrolled on the study, the median age was 68 and 69 in the single-agent and combination arms, respectively. Approximately half the total population was male (n = 64/125) and patients received a median of 1 prior line of therapy in the single-agent cohort (range, 1-5) and 2 in the combination cohort (range, 1-5). Additionally, all patients in both groups had received prior anti-CD20 therapy.

Of the 125 total patients enrolled on the study, 97 are still receiving ongoing treatment across all cohorts. In the TG-1701 monotherapy arm, 28% of patients experienced intra-patient dose escalation. In total 16% of those in the monotherapy arm and 31% of those in the combination arm, as well as 3% and 5% of those receiving the 200 mg and 300 mg doses, respectively, had a dose reduction of any agent. Moreover, 28%, 16%, 26%, and 10% of each arm, respectively, are off study.

Across most study cohorts, the most common reason for treatment discontinuation was progression by criteria. Notably, 2 patients discontinued due to non-treatment related adverse effects (AEs) in the 200 mg disease-specific cohort.

In terms of safety, the most common AEs were grade 1 to 2 in severity and few grades 3 or higher events were reported. In the dose-escalation monotherapy arm, the most common any grade AEs were respiratory tract infection (36%), constipation (32%), and bruising (28%), with common any grade hematologic and lab abnormalities including neutropenia (24%), alanine aminotransferase (ALT) increase (24%), and aspartate aminotransferase (AST) increase (20%). The most common any grade AE in both the disease-specific and CLL monotherapy cohorts was respiratory tract infection (10% for each). Common any grade hematologic and lab abnormalities included neutropenia (13%), anemia (11%), and AKT increase (8%) in the disease-specific cohort. In the CLL cohort, this included ALT increase (15%), AST increase (15%), and neutropenia (10%).

Grade 3 or higher AEs included respiratory tract infection (8%) and rash (4%) in the dose escalation cohort and COVID-19 (2% and 10%) in the disease-specific and CLL cohorts, respectively. In terms of hematologic and lab abnormalities, the most common grade 3 or higher AEs included ALT increase (12%) in the dose escalation cohort and neutropenia (8% and 10%) in the disease-specific cohorts and CLL cohorts, respectively.

In combination arm, the most common any grade AEs were diarrhea (47%), chest tightness/facial flushing (47%), bruising (47%), nausea (32%), and hypertension (32%). Grade 3 AEs included diarrhea (11%), chest tightness and flushing (5%), hypertension (5%), and nausea (5%). Moreover, 11% and 5% of patients experienced grade 4 neutropenia and ALT increase, respectively.

“In terms of laboratory abnormalities, neutropenia was the most common grade 3 or higher [event], seen in 8% of patients all together,” Cheah said.

Investigators concluded that these findings provide the rationale for further daily dosing with TG-1701.

_References

1. _{Cheah C, Jurczak W, Lasica M, et al. Updated results of the selective Bruton tyrosine kinase (BTK) inhibitor TG-1701, as monotherapy and in combination with ublituximab and umbralisib (U2) in patients (pts) with B-cell malignancies. J Clin Oncol. 2021;39(15):7525-7525. doi: 10.1200/JCO.2021.39.15_suppl.7525}

2. _{Normant E, Gorelik L, Shmeis R, et al. TG-1701 a novel, orally available, and covalently-bound BTK inhibitor. Paper presented at: EHA23 Annual Meeting; June 2018. Accessed June 5, 2021. Abstract PF638.}

3. _{Ribeiro ML, Reyes-Garau D, Vinyoles M, et al. TG-1701, a novel irreversible Bruton’s kinase (BTK) inhibitor, cooperates with ublituximab-driven ADCC and ADCP in in vitro and in vivo models of ibrutinib-resistant mantle cell lymphoma. Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting II; June 22-24, 2020. Abstract 2205.}