SAFETY AND ACTIVITY OF THE ONCE DAILY SELECTIVE BRUTON TYROSINE KINASE (BTK) INHIBITOR TG-1701 IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND LYMPHOMA.
Author(s): ,
Chan Cheah
Affiliations:
Haematology,Linear Clinical Research, and Sir Charles Gardiner Hospital,Nedlands,Australia
,
Nick Wickham
Affiliations:
Haematology,Ashford Cancer Centre Research,Adelaide,Australia
,
Costas Yannakou
Affiliations:
Department of Molecular Oncology and Cancer Immunology,Epworth HealthCare,Melbourne,Australia
,
Katharine Lewis
Affiliations:
Haematology,Linear Clinical Research, and Sir Charles Gardiner Hospital,Nedlands,Australia
,
Chi-Hung Hui
Affiliations:
Haematology,Ashford Cancer Centre Research,Adelaide,Australia
,
Pek Sang Tang
Affiliations:
Haematology,St. Vincent Hospital and University of Melbourne,Melbourne,Australia
,
Tejasvi Turpuseema
Affiliations:
Clinical Development,TG Therapeutics,New York,United States
,
Hari Miskin
Affiliations:
Clinical Development,TG Therapeutics,New York,United States
,
Jian-Ping Tang
Affiliations:
Clinical Pharmacology,TG Therapeutics,New York,United States
,
Emmanuel Normant
Affiliations:
Pre-Clinical Sciences,TG Therapeutics,New York,United States
,
Alejandro Ricart
Affiliations:
Clinical Development,TG Therapeutics,New York,United States
Constantine Tam
Affiliations:
Haematology,St. Vincent Hospital and University of Melbourne,Melbourne,Australia
(Abstract release date: 05/14/20) EHA Library. Cheah C. 06/12/20; 294623; EP705
Chan Y. Cheah
Chan Y. Cheah
Contributions
Abstract

Abstract: EP705

Type: e-Poster

Background

BTK inhibition is effective in the treatment of CLL and lymphoma but requires continuous treatment and complete responses (CR) are rare. BTK based combination regimens have the potential to increase depth of response and to permit time-limited therapy. TG-1701 is a selective, once daily (QD), covalently bound BTK inhibitor.

Aims
Herein we report the results of the dose-escalation study of TG-1701 as monotherapy and in combination with umbralisib and ublituximab (1701 + U2).

Methods

The primary objectives of the study are to characterize the safety profile and to determine the recommended Phase 2 dose of TG-1701 and TG-1701 + U2. Other objectives: assessment of pharmacokinetics (PK), antitumor activity, and pharmacodynamics. Eligible patients (pts) have B-cell malignancy relapsed/refractory to standard therapy. Treatment consists of escalating doses of oral TG-1701 QD, continuously administered in 28-day (D) cycles (C). Pts in the TG-1701 + U2 arm receive TG-1701 + umbralisib 800 mg oral QD + ublituximab 900 mg IV on D1, 8, 15 of C1, and D1 of C2 - C6. All pts are treated until disease progression, unacceptable toxicity, or withdrawal of consent.

Results

As of December 1st, 2019, 30 pts have been treated with TG-1701: 21 in the monotherapy arm, and 9 in the combination arm. Pts have received a median of 8 C of monotherapy and 5 C of combination therapy. One dose-limiting toxicity has been observed, a Grade 3 ALT increased at 400 mg QD monotherapy. This event was transient, the patient remained asymptomatic with normal liver function, and continued treatment at a reduced dose of 300 mg QD. The most common treatment-related adverse events (AE) are neutropenia, respiratory tract infection, bruising, and ALT/AST increased. There have been no treatment-related deaths nor treatment discontinuations due to AE. PK: linear kinetics are apparent over the dose range of 100 to 300 mg QD. Near complete BTK occupancy has been achieved at all dose levels. Best clinical responses by cohort are in the table below.

 

100 mg QD

200 mg QD

300 mg QD

400 mg QD

100 mg QD + U2

200 mg QD + U2

WM

1 (PR)

4 (PR, PR, SD, SD)

1 (SD)

3 (MR, MR, 1 pending)

1 (PR)

-

CLL

-

3 (PR, SD, SD)

1 (SD)

1 (PR)

-

1 (pending)

SLL

-

-

-

1 (PR)

-

-

FL

-

-

1 (SD)

1 (SD)

4 (CR, CR, PR, SD)

-

MZL

-

1 (SD)

-

-

1 (PR)

1 (pending)

MCL

1 (PR)

-

-

-

-

-

DLBCL

1 (PD)

1 (PD)

-

-

1 (PR)

-

Conclusion

TG-1701, alone and in combination with U2, has an encouraging safety profile with clinical and pharmacodynamic activity at all dose levels evaluated. This study (NCT03671590) has opened enrollment in disease-specific cohorts.

Session topic: 06. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): B cell chronic lymphocytic leukemia, B cell lymphoma, Phase I/II, Signaling

Abstract: EP705

Type: e-Poster

Background

BTK inhibition is effective in the treatment of CLL and lymphoma but requires continuous treatment and complete responses (CR) are rare. BTK based combination regimens have the potential to increase depth of response and to permit time-limited therapy. TG-1701 is a selective, once daily (QD), covalently bound BTK inhibitor.

Aims
Herein we report the results of the dose-escalation study of TG-1701 as monotherapy and in combination with umbralisib and ublituximab (1701 + U2).

Methods

The primary objectives of the study are to characterize the safety profile and to determine the recommended Phase 2 dose of TG-1701 and TG-1701 + U2. Other objectives: assessment of pharmacokinetics (PK), antitumor activity, and pharmacodynamics. Eligible patients (pts) have B-cell malignancy relapsed/refractory to standard therapy. Treatment consists of escalating doses of oral TG-1701 QD, continuously administered in 28-day (D) cycles (C). Pts in the TG-1701 + U2 arm receive TG-1701 + umbralisib 800 mg oral QD + ublituximab 900 mg IV on D1, 8, 15 of C1, and D1 of C2 - C6. All pts are treated until disease progression, unacceptable toxicity, or withdrawal of consent.

Results

As of December 1st, 2019, 30 pts have been treated with TG-1701: 21 in the monotherapy arm, and 9 in the combination arm. Pts have received a median of 8 C of monotherapy and 5 C of combination therapy. One dose-limiting toxicity has been observed, a Grade 3 ALT increased at 400 mg QD monotherapy. This event was transient, the patient remained asymptomatic with normal liver function, and continued treatment at a reduced dose of 300 mg QD. The most common treatment-related adverse events (AE) are neutropenia, respiratory tract infection, bruising, and ALT/AST increased. There have been no treatment-related deaths nor treatment discontinuations due to AE. PK: linear kinetics are apparent over the dose range of 100 to 300 mg QD. Near complete BTK occupancy has been achieved at all dose levels. Best clinical responses by cohort are in the table below.

 

100 mg QD

200 mg QD

300 mg QD

400 mg QD

100 mg QD + U2

200 mg QD + U2

WM

1 (PR)

4 (PR, PR, SD, SD)

1 (SD)

3 (MR, MR, 1 pending)

1 (PR)

-

CLL

-

3 (PR, SD, SD)

1 (SD)

1 (PR)

-

1 (pending)

SLL

-

-

-

1 (PR)

-

-

FL

-

-

1 (SD)

1 (SD)

4 (CR, CR, PR, SD)

-

MZL

-

1 (SD)

-

-

1 (PR)

1 (pending)

MCL

1 (PR)

-

-

-

-

-

DLBCL

1 (PD)

1 (PD)

-

-

1 (PR)

-

Conclusion

TG-1701, alone and in combination with U2, has an encouraging safety profile with clinical and pharmacodynamic activity at all dose levels evaluated. This study (NCT03671590) has opened enrollment in disease-specific cohorts.

Session topic: 06. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): B cell chronic lymphocytic leukemia, B cell lymphoma, Phase I/II, Signaling

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