ACALABRUTINIB, A SECOND-GENERATION BRUTON TYROSINE KINASE (BTK) INHIBITOR, IN PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Author(s): ,
William Wierda
Affiliations:
University of Texas MD Anderson Cancer Center,Houston,United States
,
Jeffrey Jones
Affiliations:
The Ohio State University,Columbus,United States
,
Richard Furman
Affiliations:
Weill Cornell Medical College,New York,United States
,
Deborah Stephens
Affiliations:
Univ of Utah Huntsman Cancer Inst,Salt Lake City,United States
,
Steve Devereux
Affiliations:
College Hospital,London,United Kingdom
,
Jennifer Brown
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Peter Hillmen
Affiliations:
St. James's University Hospital,Leeds,United Kingdom
,
Ahmed Hamdy
Affiliations:
Acerta Pharma,Redwood City,United States
,
Maria Fardis
Affiliations:
Acerta Pharma,Redwood City,United States
,
Manal Tawashi
Affiliations:
Acerta Pharma,Redwood City,United States
,
Min Hui Wang
Affiliations:
Acerta Pharma,Redwood City,United States
,
Priti Patel
Affiliations:
Acerta Pharma,Redwood City,United States
,
Diana Mittag
Affiliations:
Acerta Pharma,Oss,Netherlands
,
Fanny Krantz
Affiliations:
Acerta Pharma,Redwood City,United States
,
Wayne Rothbaum
Affiliations:
Acerta Pharma,Redwood City,United States
,
Raquel Izumi
Affiliations:
Acerta Pharma,Redwood City,United States
,
Susan O'Brien
Affiliations:
University of California–Irvine,Irvine,United States
John Byrd
Affiliations:
The Ohio State University,Columbus,United States
(Abstract release date: 05/19/16) EHA Library. Wierda W. 06/11/16; 135187; S431
Dr. William Wierda
Dr. William Wierda
Contributions
Abstract
Abstract: S431

Type: Oral Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45

Location: Hall A1

Background
Btk is a kinase involved in B-cell receptor signaling and a critical therapeutic target in CLL. Acalabrutinib—an irreversible, selective Btk inhibitor has demonstrated clinical efficacy in relapsed CLL (Byrd NEJM 2015).

Aims
Here, we present preliminary results from an ongoing Phase 1-2 study of acalabrutinib monotherapy in patients (pts) with previously untreated CLL.

Methods
Pts with previously untreated CLL who met IWCLL 2008 criteria for treatment were eligible, irrespective of any cytopenias. Pts received oral acalabrutinib at 100 mg BID (n = 37) or 200 mg QD (n = 37). Pts had a median age of 64 (48-85) years, bulky lymph nodes ≥ 5 cm (47%) and unmutated IGHV gene (57%, 38/67). CLL responses were assessed per modified IWCLL criteria.

Results
Results are presented through 07Dec2015 for the first 74 treated pts, including 72 evaluable for response. Median time on study (N = 74) was 11 (1-15) months. Acalabrutinib was well tolerated with 97% (72/74) of pts continuing on study drug. Most AEs were Grade (Gr) ≤ 2. The most common Gr 1-2 AEs ( ≥ 15% pts) were headache (42%), diarrhea (35%), arthralgia (22%), contusion (18%), nausea (18%) and increased weight (18%). Gr 3-4 AEs that occurred in ≥ 2 pts were syncope (n = 2, both Gr 3) and hypertension (n = 2, both Gr 3). One Gr 5 event (pneumonia) has occurred. One Gr 3 upper GI bleed due to a gastric ulcer and aspirin use has occurred. No atrial fibrillation was reported. Clinical activity was observed with both dose schedules; Btk occupancy was highest with BID dosing (98% vs 93% predose at Day 28). All pts had a rapid reduction in lymphadenopathy. Treatment-related lymphocytosis occurred in 53% (39/74) of pts and resolved in 97% (38/39) of these pts. In general, lymphocytosis peaked at a median of 1 week and resolved by a median of 7 (3-15) weeks. Best ORR was 96% (PR = 86%, PR+L = 10%, SD = 4%, PD = 0%). Median time to response was 2 (2-8) months. No CLL progression or Richter’s transformation have occurred.

Conclusion
In pts with previously untreated CLL, a favorable safety profile and high response rates that appear durable were observed with acalabrutinib therapy. Based on these results, a Phase 3 trial has commenced (NCT02475681).

Session topic: Innovative therapies in CLL

Keyword(s): B cell chronic lymphocytic leukemia, Kinase inhibitor
Abstract: S431

Type: Oral Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 12:30 - 12:45

Location: Hall A1

Background
Btk is a kinase involved in B-cell receptor signaling and a critical therapeutic target in CLL. Acalabrutinib—an irreversible, selective Btk inhibitor has demonstrated clinical efficacy in relapsed CLL (Byrd NEJM 2015).

Aims
Here, we present preliminary results from an ongoing Phase 1-2 study of acalabrutinib monotherapy in patients (pts) with previously untreated CLL.

Methods
Pts with previously untreated CLL who met IWCLL 2008 criteria for treatment were eligible, irrespective of any cytopenias. Pts received oral acalabrutinib at 100 mg BID (n = 37) or 200 mg QD (n = 37). Pts had a median age of 64 (48-85) years, bulky lymph nodes ≥ 5 cm (47%) and unmutated IGHV gene (57%, 38/67). CLL responses were assessed per modified IWCLL criteria.

Results
Results are presented through 07Dec2015 for the first 74 treated pts, including 72 evaluable for response. Median time on study (N = 74) was 11 (1-15) months. Acalabrutinib was well tolerated with 97% (72/74) of pts continuing on study drug. Most AEs were Grade (Gr) ≤ 2. The most common Gr 1-2 AEs ( ≥ 15% pts) were headache (42%), diarrhea (35%), arthralgia (22%), contusion (18%), nausea (18%) and increased weight (18%). Gr 3-4 AEs that occurred in ≥ 2 pts were syncope (n = 2, both Gr 3) and hypertension (n = 2, both Gr 3). One Gr 5 event (pneumonia) has occurred. One Gr 3 upper GI bleed due to a gastric ulcer and aspirin use has occurred. No atrial fibrillation was reported. Clinical activity was observed with both dose schedules; Btk occupancy was highest with BID dosing (98% vs 93% predose at Day 28). All pts had a rapid reduction in lymphadenopathy. Treatment-related lymphocytosis occurred in 53% (39/74) of pts and resolved in 97% (38/39) of these pts. In general, lymphocytosis peaked at a median of 1 week and resolved by a median of 7 (3-15) weeks. Best ORR was 96% (PR = 86%, PR+L = 10%, SD = 4%, PD = 0%). Median time to response was 2 (2-8) months. No CLL progression or Richter’s transformation have occurred.

Conclusion
In pts with previously untreated CLL, a favorable safety profile and high response rates that appear durable were observed with acalabrutinib therapy. Based on these results, a Phase 3 trial has commenced (NCT02475681).

Session topic: Innovative therapies in CLL

Keyword(s): B cell chronic lymphocytic leukemia, Kinase inhibitor

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