Promising clinical activity observed in single agent and combination TG-1701 in CLL and other malignant B cell tumors

Encouraging clinical and pharmacodynamic activity was observed 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) which were presented virtually at the ASCO 2021 annual meeting.1

The maximum tolerated dose of the BTK inhibitor was not reached in patients who received TG-1701 as monotherapy up to a dose of 400 mg per day (QD). The dose-escalation cohort, which administered 100 mg to 400 mg of TG-1701 as monotherapy once daily, 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, gave an ORR of 95% after a median follow-up of 12.2 months in patients with lymphoid leukemia chronic (CLL), 65% in patients with mantle cell lymphoma (MCL) and 95% in patients with Waldenström’s macroglobulinemia.

In the CLL cohort, a dose of 300 mg as monotherapy gave an ORR of 100% at a median follow-up of 8.6 months. In addition, a rising dose cohort that combined 100 mg-300 mg of TG-1701 with ublituximab (TGTX-1101) and umbralisib (Ukoniq) QD achieved an ORR of 79% with a median follow-up of 15, 6 months on multiple B. cell malignancies, with a complete response rate (CR) was 21%.

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

While patients with CLL and other B cell malignancies have benefited from treatment with BTK inhibitor monotherapies, CRs and deep remissions remain rare. TG-1701 is a covalently linked BTK inhibitor that has demonstrated superior selectivity over other agents, such as ibrutinib (Imbruvica). In addition, in vitro and in vivo data demonstrated increased susceptibility to inhibition when combined with ublituximab / umbralisib in BTK resistant xenograft models.2.3

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

The trial included patients who had relapsed or were refractory to prior standard therapy and who presented with CLL or histologically confirmed B-cell lymphoma, warranting systemic therapy. Disease-specific study cohorts allowed treatment-naïve patients to enroll if they were unsuitable for standard first-line chemoimmunotherapy. Adequate organ function was also required. In addition, patients who had received previous treatment with a BTK inhibitor, or who had other severe or uncontrolled disease, were unable to participate in the study. Patients receiving concomitant warfarin (Jantoven) therapy were also excluded from the trial, although other anticoagulants were permitted.

The dose escalation portion of the trial included a TG-1701 monotherapy cohort and a TG-1701 plus ublituximab / umbralisib combination cohort. Once the optimal dose was determined, the trial then focused on disease-specific cohorts, which looked at both monotherapy and combination regimens.

Oral TG-1701 was administered continuously once daily in 28-day cycles. In addition, intra-patient dose escalation was permitted in the arms as monotherapy. In the combination arm, an escalating dose of TG-1701 was administered once daily, plus an oral dose of umbralisib 800 mg or 600 mg once daily and an intravenous dose of ublituximab 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 every 3 cycles thereafter.

In the dose escalating monotherapy cohort, patients received TG-1701 100 mg once daily (n = 3), 200 mg daily (n = 9; LLC, n = 20; MCL, n = 21; Waldenström’s macroglobulinemia n = 21), 300 mg QD (n = 3; LLC, n = 20) and 400 mg QD (n = 10).

In the escalating dose combination cohort, patients received TG-1701 at 100 mg QD (n = 7) and 200 mg QD (n = 6) plus ublituximab / umbralisib. In addition, patients in the cohort who received TG-1701 at 300 mg once daily (n = 6) also received umbralisib at a dose of 600 mg once daily, plus ublituximab at the designated test dose.

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

Of the total 125 patients enrolled in the study, 97 are still receiving ongoing treatment across all cohorts. In the TG-1701 monotherapy arm, 28% of patients underwent an 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. Additionally, 28%, 16%, 26%, and 10% of each arm, respectively, are not being investigated.

In most study cohorts, the most common reason for discontinuing treatment was progression according to criteria. Notably, 2 patients discontinued due to unrelated adverse reactions (AEs) in the 200 mg disease specific cohort.

In terms of safety, the most common AEs were grade 1 to 2 severity and few grade 3 or more events were reported. In the dose-escalating monotherapy arm, the most common AEs of any grade were respiratory tract infection (36%), constipation (32%), and bruising (28%), with common hematologic and laboratory abnormalities. of any grade, including neutropenia (24%). , increased alanine aminotransferase (ALAT) (24%) and increased aspartate aminotransferase (AST) (20%). The most common AE of any grade in disease-specific monotherapy cohorts and CLL was respiratory tract infection (10% each). Common hematologic and laboratory abnormalities of any grade included neutropenia (13%), anemia (11%), and increased AKT (8%) in the disease-specific cohort. In the CLL cohort, this included an increase in ALT (15%), an increase in AST (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 specific cohorts. disease and LLC, respectively. In terms of hematologic and laboratory abnormalities, the most common grade 3 or higher AEs included increased ALT (12%) in the dose escalation cohort and neutropenia (8% and 10%) in the cohorts disease-specific and CLL cohorts, respectively.

In the combined arm, the most common adverse reactions of any grade 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%). Additionally, 11% and 5% of patients experienced grade 4 neutropenia and increased ALT, respectively.

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

The investigators concluded that these results justify the daily administration of TG-1701.

The references
  1. Cheah C, Jurczak W, Lasica M, et al. Updated results of Bruton selective tyrosine kinase inhibitor (BTK) TG-1701, as monotherapy and in combination with ublituximab and umbralisib (U2) in patients (pts) with malignant B-cell tumors . 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, covalently linked BTK inhibitor. Document presented to: 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 Kinase (BTK) Inhibitor, Cooperates with Oblituximab-induced 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.

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