TG-1701 A selective bruton tyrosine kinase (btk) inhibitor, as monotherapy and in combination with ublituximab and umbralisib (u2) in chronic lymphocytic leukemia (cll) and lymphoma

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-na.ve (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. Aims: The primary objectives of the study are to characterize the safety profile and define the recommended Ph 2 doses for the drugs alone and in combination. Methods: Patients with R/R CLL, MCL and Waldenstr.m's (WM) were enrolled in an ongoing Ph1 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 patients were treated until disease progression, unacceptable toxicity, or investigator/ patient decision to withdraw. Results: As of 03 February 2021,123 patients 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), and17 in the1701+U2 DE arm. The median # of prior therapies was1 (range,1 -10). All patients were BTKi-na.ve. All123 patients were evaluable for safety. TG-1701 was well tolerated and the maximum tolerated dose (MTD) for monotherapy was not reached at 400 mg (demonstrating near100% saturation of the BTK at all dose levels studied). Treatment emergent adverse events (TEAE) of clinical interest included atrial fibrillation (AF 4.0% of patients, G ≥3 in1 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 patients. TEAEs leading to treatment discontinuation occurred in1.6% of patients (AF, COVID-19). At the data cut-off,119 patients 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) was15.9 mos (1.3 - 28.6+) in DE and 8.5 mos (1.4 -15.6+) in disease-specific cohorts. No complete responses (CR) were confirmed on TG-1701 monotherapy. The objective response rate (ORR) for1701+U2 was 82.3% with a 23.5% CR rate. Best change from baseline in tumor burden in patients in the1701+U2 combination arm is presented in the figure below. Table. Response per investigator review by treatment group DE arm (N = 23) 200 mg CLL (N = 20) 200 mg MCL (N = 20) 200 mg WM (N = 20) 300 mg CLL (N =19)1701+U2 DE arm (N =17) ORR, % 56.5 95.0 60.0 95.0100 82.3 CR, % 0 0 0 0 0 23.5 Very good PR, % 4.3 0 5.9 PR, % 47.8 95.0 60.0 70.0100 52.9 Minor response, % 4.3 25.0 0 mFU mos17.511.6 8.2 9.7 5.814.3 Summary/Conclusion: TG-1701 exhibits an encouraging safety and efficacy profile. The combination of1701+U2 has been well tolerated and dose escalation continues. The combination shows enhanced depth of response over TG-1701 monotherapy. Recruitment to this study (NCT03671590) continues.