CHEMO-FREE TRIPLET COMBINATION OF TGR-1202, UBLITUXIMAB, AND IBRUTINIB IS WELL TOLERATED AND HIGHLY ACTIVE IN PATIENTS WITH ADVANCED CLL AND NHL
Author(s): ,
Loretta Nastoupil
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Matthew A. Lunning
Affiliations:
University of Nebraska Medical Center,Omaha,United States
,
Julie M. Vose
Affiliations:
University of Nebraska Medical Center,Omaha,United States
,
Marshall T. Schreeder
Affiliations:
Clearview Cancer Institute,Huntsville,United States
,
Tanya Siddiqi
Affiliations:
City of Hope National Medical Center,Duarte,United States
,
Christpher R. Flowers
Affiliations:
Emory University/Winship Cancer Institute,Atlanta,United States
,
Jonathan B. Cohen
Affiliations:
Emory University/Winship Cancer Institute,Atlanta,United States
,
Jan A. Burger
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
William G. Wierda
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Susan O'Brien
Affiliations:
University of California Irvine Cancer Center,Orange,United States
,
Peter Sportelli
Affiliations:
TG Therapeutics, Inc.,New York,United States
,
Hari P. Miskin
Affiliations:
TG Therapeutics, Inc.,New York,United States
,
Michelle A. Purdom
Affiliations:
TG Therapeutics, Inc.,New York,United States
,
Michael S. Weiss
Affiliations:
TG Therapeutics, Inc.,New York,United States
Nathan Fowler
Affiliations:
MD Anderson Cancer Center,Houston,United States
(Abstract release date: 05/18/17) EHA Library. Nastoupil L. 06/25/17; 182059; S772
Loretta Nastoupil
Loretta Nastoupil
Contributions
Abstract

Abstract: S772

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:45 - 09:00

Location: Hall A

Background
Novel targeted agents are emerging for B-cell malignancies, but few studies have safely combined these agents.  Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen.  TGR-1202 is a next generation, once daily, PI3Kδ inhibitor, demonstrating a favorable safety profile compared to prior inhibitors, including in long-term follow up (Burris, 2016). 

Aims
This Ph 1 trial evaluates the safety/efficacy of the triplet combination of a novel anti-CD20 mAb + PI3Kδ + BTK inhibitor (ibrutinib) in pts with B-cell malignancies.

Methods
Eligible pts had CLL or rel/ref NHL w/o limit to prior therapies, including those ref to prior PI3Kδ or BTK inhibitors.  UTX dosed on D 1, 8, 15 of C 1, D 1 of C 2-6, and C 9 & 12.  TGR-1202 dose escalated (400/600/800mg QD), ibrutinib dosed at 420mg (CLL) or 560mg (NHL), both on C1D1.

Results

38 pts were enrolled: 20 CLL/SLL and 18 NHL, including 6 follicular (FL), 6 DLBCL, 4 mantle cell (MCL) and 2 marginal zone (MZL).  Med age 65 yrs (range 32-85); 29 M/9 F; med prior tx = 3 (range 0-6).  2 pts ref to prior PI3Kδ /2 prev treated with ibrutinib (1 ref/1 rel).  MTD was not reached.  Most common (> 20%) all causality AE’s were fatigue (42%), diarrhea (39%), dizziness (34%), nausea (32%), neutropenia, pyrexia, rash, infusion reaction, insomnia (each at 29%), thrombocytopenia, cough (each at 26%), anemia (24%) and sinusitis (21%).  GR 3/4 AE’s (all causality) were minimal, the only event >10% was neutropenia (16%).  ORR amongst 36 evaluable pts was as follows:
Subtype
N
CR
PR
ORR
CLL/SLL
19
3
16
100%
FL/MZL
7
2
4
86%
DLBCL
6
0
1
17%
MCL
4
1
3
100%
 
53% of evaluable CLL pts had high-risk cytogenetics and 4/6 DLBCL pts were non-GCB.  One CLL pt (17p/11q del) ref to PI3Kδ and ibrutinib achieved a CR.  Med time on study is 10 mos (range 1 – 27 mos).  Med DOR not reached (range 3 – 24 mos).

Conclusion
This is the first known triplet combination of an anti-CD20 mAb + PI3Kδ + BTK inhibitor. The combination of UTX, TGR-1202, and ibrutinib has been well tolerated with activity observed across heavily pre-treated and high-risk B-cell malignancies.  Expansion cohorts at the highest dose (800mg TGR-1202 + full dose ibrutinib) are underway.  Future trials for the triplet are warranted.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): CD20, B cell, PI3K

Abstract: S772

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:45 - 09:00

Location: Hall A

Background
Novel targeted agents are emerging for B-cell malignancies, but few studies have safely combined these agents.  Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen.  TGR-1202 is a next generation, once daily, PI3Kδ inhibitor, demonstrating a favorable safety profile compared to prior inhibitors, including in long-term follow up (Burris, 2016). 

Aims
This Ph 1 trial evaluates the safety/efficacy of the triplet combination of a novel anti-CD20 mAb + PI3Kδ + BTK inhibitor (ibrutinib) in pts with B-cell malignancies.

Methods
Eligible pts had CLL or rel/ref NHL w/o limit to prior therapies, including those ref to prior PI3Kδ or BTK inhibitors.  UTX dosed on D 1, 8, 15 of C 1, D 1 of C 2-6, and C 9 & 12.  TGR-1202 dose escalated (400/600/800mg QD), ibrutinib dosed at 420mg (CLL) or 560mg (NHL), both on C1D1.

Results

38 pts were enrolled: 20 CLL/SLL and 18 NHL, including 6 follicular (FL), 6 DLBCL, 4 mantle cell (MCL) and 2 marginal zone (MZL).  Med age 65 yrs (range 32-85); 29 M/9 F; med prior tx = 3 (range 0-6).  2 pts ref to prior PI3Kδ /2 prev treated with ibrutinib (1 ref/1 rel).  MTD was not reached.  Most common (> 20%) all causality AE’s were fatigue (42%), diarrhea (39%), dizziness (34%), nausea (32%), neutropenia, pyrexia, rash, infusion reaction, insomnia (each at 29%), thrombocytopenia, cough (each at 26%), anemia (24%) and sinusitis (21%).  GR 3/4 AE’s (all causality) were minimal, the only event >10% was neutropenia (16%).  ORR amongst 36 evaluable pts was as follows:
Subtype
N
CR
PR
ORR
CLL/SLL
19
3
16
100%
FL/MZL
7
2
4
86%
DLBCL
6
0
1
17%
MCL
4
1
3
100%
 
53% of evaluable CLL pts had high-risk cytogenetics and 4/6 DLBCL pts were non-GCB.  One CLL pt (17p/11q del) ref to PI3Kδ and ibrutinib achieved a CR.  Med time on study is 10 mos (range 1 – 27 mos).  Med DOR not reached (range 3 – 24 mos).

Conclusion
This is the first known triplet combination of an anti-CD20 mAb + PI3Kδ + BTK inhibitor. The combination of UTX, TGR-1202, and ibrutinib has been well tolerated with activity observed across heavily pre-treated and high-risk B-cell malignancies.  Expansion cohorts at the highest dose (800mg TGR-1202 + full dose ibrutinib) are underway.  Future trials for the triplet are warranted.

Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical

Keyword(s): CD20, B cell, PI3K

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