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|Title:||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.|
|Epworth Authors:||Yannakou, Costas|
|Other Authors:||Cheah, Chan|
Wickham, Nicholas W.
Andrzej Walewski,, Jan
Lewis, Katharine L.
Miskin, Hari P.
O'Connor, Owen A.
Ricart, Alejandro Daniel
Tam, Constantine Si Lun
Chronic Lymphocytic Leukemia
Mentle Cell Lymphoma
Treatment Emergent Adverse Events
Epworth Centre for Immunotherapies and Snowdome Laboratories
Molecular Oncology and Cancer Immunology
Cancer Services Clinical Institute, Epworth HealthCare, Australia
|Publisher:||American Society of Clinical Oncology|
|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: 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. Recruitment to this study continues. Response per investigator review by treatment group. Clinical trial information: NCT03671590.|
|Journal Title:||Journal of Clinical Oncology|
|Affiliated Organisations:||Sir Charles Gardiner Hospital, Comprehensive Cancer Centre, Nedlands, Australia|
Maria Sklodowska-Curie National Institute of Oncology, Krakow, Poland
St. Vincent’s Hospital Sydney, Darlinghurst, Australia
Ashford Cancer Centre Research, Adelaide, Australia
Department of Hematology, Wroclaw Medical University, Wroclaw, Poland
Hematology Department, St John’s Cancer Centre, Lublin, Poland
TG Therapeutics, Inc., New York, NY
Inst Onc Henry Moore, Buenos Aires, Argentina
St. Vincent's Hospital and University of Melbourne, Melbourne, Australia
|Type of Clinical Study or Trial:||Review|
|Appears in Collections:||Cancer Services|
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