A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma.
OBJECTIVE
Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N = 55) with single-agent abexinostat in relapsed/refractory lymphoma.


METHODS
In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m(2) twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/refractory follicular lymphoma or mantle cell lymphoma.


RESULTS
The recommended phase II dose was 45 mg/m(2) twice daily (90 mg/m(2) total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigator-assessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2-22.3+). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment-related adverse events (phase II) with ≥ 10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths.


CONCLUSIONS
The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population.
Division of Hematology/Oncology, Tufts Medical Center, Boston, Massachusetts. AEvens@tuftsmedicalcenter.org.
Andrew M
AM
Evens
Pharmacyclics, Sunnyvale, California.
Sriram
S
Balasubramanian
University of Nebraska Medical Center, Omaha, Nebraska.
Julie M
JM
Vose
Horizon Oncology Center, Lafayette, Indiana.
Wael
W
Harb
Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Leo I
LI
Gordon
Nebraska Methodist Hospital, Omaha, Nebraska.
Robert
R
Langdon
Department of Medicine, Vermont Cancer Center, University of Vermont, Burlington, Vermont.
Julian
J
Sprague
Pharmacyclics, Sunnyvale, California.
Mint
M
Sirisawad
Pharmacyclics, Sunnyvale, California.
Chitra
C
Mani
Pharmacyclics, Sunnyvale, California.
Jeanne
J
Yue
Pharmacyclics, Sunnyvale, California.
Ying
Y
Luan
Pharmacyclics, Sunnyvale, California.
Sharon
S
Horton
Pharmacyclics, Sunnyvale, California.
Thorsten
T
Graef
Washington University School of Medicine, St. Louis, Missouri.
Nancy L
NL
Bartlett
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D012008:Recurrence
D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C512352:abexinostat