ABSTRACT
Introduction: TG-1701 is an irreversible, selective, novel Bruton's tyrosine kinase inhibitor (BTKi) administered once daily (QD). BTK inhibitors, as well as the U2 combination (anti-CD20 mAb ublituximab + the PI3Kδ-CK1ϵ inhibitor umbralisib), are highly efficacious in chronic lymphocytic leukemia (CLL), each of which have been previously demonstrated to be superior over standard chemoimmunotherapy. Treatment with a more selective BTK inhibitor could result in improved efficacy and safety outcomes compared with ibrutinib (ALPINE study, EHA 2021), and we hypothesized that dual blockade of the B-cell receptor (BCR) pathway through combination of TG-1701 with U2 may confer greater depth of response compared to either regimen alone. Methods: Patients with CLL and non-Hodgkin lymphoma (NHL) were enrolled in an ongoing Phase 1 study. After characterizing the safety profile of TG-1701 monotherapy, a parallel dose escalation arm of TG-1701+U2 was implemented. Select dose levels of TG-1701 monotherapy and TG-1701+U2 were also expanded. All patients were treated until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw. Safety was evaluated in all treated patients, and efficacy was evaluated in all treated patients who had at least 1 post-baseline assessment. TG-1701 monotherapy data were previously presented;herein we present data from the TG-1701+U2 dose escalation/expansion and the TG-1701 monotherapy CLL expansion cohorts Results: As of July 2021, 142 patients were treated with TG-1701, 36 of whom were enrolled in the TG-1701+U2 arm. The median # of prior therapies across all treated patients was 1 (range, 0-10) and all patients were BTKi-naïve. Among the 36 patients treated with U2+1701, 19 were evaluable for efficacy and safety (17 too early to evaluate). The median age was 69 years (range 47-81), and 56% were male. TG-1701+U2 was well tolerated at 4 different dose levels without dose-limiting toxicities. The most common (>30%) all-causality, all grade treatment-emergent adverse events (TEAEs) were diarrhea (53%) contusion (42%), nausea (37%), hypertension, ALT/AST increase, and fatigue (all 32% each) with TG-1701+U2. Grade 3/4 AEs >15% were limited to ALT/AST increase (21%). Dose reduction occurred in 1 patient due to an AE, and 4 patients discontinued at least 1 study drug due to an AE: 2 discontinued umbralisib, 1 discontinued umbralisib and TG-1701, and 1 discontinued all 3 agents. At the data cut-off, overall response rate (ORR) was 84% (4 CR and 12 PR) among 19 evaluable patients, with remaining patients awaiting post-baseline assessment. In the monotherapy CLL-specific cohorts (200 mg QD, n=20;and 300 mg QD, n=20), 40 pts were evaluable for safety, and 39 for efficacy (1 pt withdrew due to COVID prior to first response assessment). The median age was 71 (range 49-86), and 43% were male. The most common TEAEs were increased ALT/AST (all grades: 18%;grade ≥3: 3%), followed by diarrhea (all grades: 15%;grade ≥3: none), and neutropenia (all grades: 13%;grades ≥3: 13%). There were no cases of atrial fibrillation, major bleeding, or ventricular tachyarrhythmia in the CLL cohorts at a median follow-up of 12.8 months (range 2.5 - 20.8). TEAEs leading to TG-1701 dose reduction occurred in 1 (3%) patient. No patients in the 200 mg or 300 mg CLL cohorts have discontinued due to AEs. In patients with anemia and thrombocytopenia at baseline, sustained improvement in hematologic variables was observed. The ORR among 39 patients was 97% (all PR/PR-L). Lymphocytosis resolved to normal value or <50% of baseline in 69% (24 of 35 of patients with lymphocytosis). Consistent response rates were observed across all subgroups, including the following high-risk genomic features: del17p/TP53 mutations, unmutated immunoglobulin heavy-chain variable-region (IGHV), and complex karyotype (defined as 3 ≤cytogenetic abnormalities). The median duration of response has not been reached in either cohort. Best change in tumor burden from baseline in patients with CLL is presented in Figure 1. C nclusions: TG-1701 exhibits an encouraging safety and efficacy profile as monotherapy in patients with CLL and additionally shows promising activity and a manageable tolerability profile in combination with U2. Future registration trials are being planned in CLL with TG-1701. Recruitment to this study (NCT03671590) continues. (Figure Presented).
ABSTRACT
Background: TG-1701 is a selective, covalent BTK inhibitor administered once daily (QD). Both the 'U2' combination (anti-CD20 mAb ublituximab + the PI3Kδ-CK1ϵ inhibitor umbralisib) and BTK inhibition are highly active in treatment-naïve (TN) and relapsed/refractory (R/R) CLL, each having previously demonstrated superiority over standard chemoimmunotherapy. Here we report the results of the dose escalation of TG-1701 monotherapy and TG-1701+U2. Methods: Pts with R/R CLL and lymphoma were enrolled in a Ph 1 study initially evaluating dose escalation (DE) of oral TG-1701 QD continuously administered in 28-day cycles (100, 200, 300, and 400 mg). After characterizing the safety profile of TG-1701 monotherapy, we implemented a parallel DE arm of TG-1701+U2. Select dose levels of TG-1701 monotherapy were expanded in CLL, MCL and Waldenström's (WM). All pts were treated until disease progression. The primary objectives are to characterize the safety profile and define the recommended Ph 2 doses for the drugs alone and in combination. Results: As of 03 February 2021, 123 pts were treated with TG-1701: 25 in the monotherapy DE arm, 61 in the 200 mg disease-specific cohorts (20 CLL [5 TN], 21 MCL [4 TN], 20 WM [8 TN]), 20 in the 300 mg CLL cohort (4 TN), and 17 in the 1701+U2 DE arm. The median # of prior therapies was 1 (range, 1 -10). All pts were BTKi-naïve. All 123 pts were evaluable for safety. TG-1701 was well tolerated and the maximum tolerated dose (MTD) for monotherapy was not reached at 400 mg (demonstrating near 100% saturation of the BTK at all dose levels studied). Treatment emergent adverse events (TEAE) of clinical interest included atrial fibrillation (AF 4.0% of pts, G ≥3 in 1 case), G ≥3 hypertension (2.4%), and bleeding events (18.7%, all G1-2). No cases of ventricular tachyarrhythmia were reported. TEAEs leading to TG-1701 dose reduction occurred in 6.5% of pts. TEAEs leading to treatment discontinuation occurred in 1.6% of pts (AF, COVID-19). At the data cut-off, 119 pts were evaluable for response, including 40 in DE (Table). The median duration of response has not been reached among responders overall. The median follow-up (mFU range) was 15.9 mos (1.3 -28.6+) in DE and 8.5 mos (1.4 -15.6+) in disease-specific cohorts. Conclusions: TG1701 exhibits an encouraging safety and efficacy profile. The combination of 1701+U2 has been well tolerated and dose escalation continues. The combination shows enhanced depth of response over TG-1701 monotherapy. Recruitment to this study continues. Response per investigator review by treatment group.
ABSTRACT
Introduction: TG-1701 is a selective, covalent BTK inhibitor administered once daily (QD). Both the “U2” combination (anti-CD20 mAb ublituximab + the PI3Kδ-CK1ϵ inhibitor umbralisib) and BTK inhibition are highly active in treatment-naïve (TN) and relapsed/ refractory (R/R) CLL, each having previously demonstrated superiority over standard chemoimmunotherapy. Herein we report the results of the dose escalation of TG-1701 monotherapy and TG-1701+U2. Methods: Patients (pts) with R/R CLL, MCL and Waldenström's (WM) were enrolled in an ongoing Ph 1 study initially evaluating dose escalation (DE) of oral TG-1701 QD continuously administered in 28-day cycles (100, 200, 300, and 400 mg). After characterizing the safety profile of TG-1701 monotherapy, we implemented a parallel DE arm of TG-1701+U2. Select dose levels of TG-1701 monotherapy were expanded. All pts were treated until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw. Results: As of 03 February 2021, 123 pts were treated with TG-1701 as follows: 25 in the monotherapy DE arm, 61 in the 200 mg disease-specific cohorts (20 CLL [5 TN], 21 MCL [4 TN], 20 WM [8 TN]), 20 in the 300 mg CLL cohort (4 TN), and 17 in the 1701+U2 DE arm. The median # of prior therapies was 1 (range, 1-10). All pts were BTKi-naïve. All 123 pts were evaluable for safety. TG-1701 was well tolerated and the maximum tolerated dose (MTD) for monotherapy was not reached at 400 mg (demonstrating near 100% saturation of the BTK at all dose levels studied). Treatment emergent adverse events (TEAE) of clinical interest included atrial fibrillation (AF 4.0% of pts, G ≥3 in 1 case), G ≥3 hypertension (2.4%), and bleeding events (18.7%, all G1-2). No cases of ventricular tachyarrhythmia were reported. TEAEs leading to TG-1701 dose reduction occurred in 6.5% of pts. TEAEs leading to treatment discontinuation occurred in 1.6% of pts (AF, COVID-19). At the data cut-off, 119 pts were evaluable for response, including 40 in DE (Table). The median duration of response has not been reached among responders overall. The median follow-up (mFU range) was 15.9 mos (1.3-28.6+) in DE and 8.5 mos (1.4-15.6+) in disease-specific cohorts. Best change from baseline in tumor burden in pts in the 1701+U2 combination arm is presented in the figure below. Conclusions: TG-1701 exhibits an encouraging safety and efficacy profile. The combination of 1701+U2 has been well tolerated and dose escalation continues. The combination shows enhanced depth of response over TG-1701 monotherapy.