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A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma Andrew M

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A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma Andrew M Published OnlineFirst October 19, 2015; DOI: 10.1158/1078-0432.CCR-15-0624 Cancer Therapy: Clinical Clinical Cancer Research A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma Andrew M. Evens1, Sriram Balasubramanian2, Julie M. Vose3, Wael Harb4, Leo I. Gordon5, Robert Langdon6, Julian Sprague7, Mint Sirisawad2, Chitra Mani2, Jeanne Yue2,Ying Luan2, Sharon Horton2, Thorsten Graef2, and Nancy L. Bartlett8 Abstract Purpose: Additional targeted therapeutics are needed for the 86% of follicular lymphoma patients with an investigator- treatment of lymphoma. Abexinostat is an oral pan-histone dea- assessed ORR of 64.3% for evaluable patients [intent-to-treat cetylase inhibitor (HDACi) displaying potent activity in preclinical (ITT) ORR 56.3%]. Median duration of response was not reached, models. We conducted a multicenter phase I/II study (N ¼ 55) with and median progression-free survival (PFS) was 20.5 months single-agent abexinostat in relapsed/refractory lymphoma. (1.2–22.3þ). Of responding follicular lymphoma patients, Experimental Design: In phase I, 25 heavily pretreated patients 89% were on study/drug >8 months. In mantle cell lymphoma, with any lymphoma subtype received oral abexinostat ranging the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and from 30 to 60 mg/m2 twice daily 5 days/week for 3 weeks or 7 median PFS was 3.9 months (range, 0.1–11.5). Grade 3–4 treat- days/week given every other week. Phase II evaluated abexinostat ment-related adverse events (phase II) with 10% incidence were at the maximum tolerated dose in 30 patients with relapsed/ thrombocytopenia (20%), fatigue (16.7%), and neutropenia refractory follicular lymphoma or mantle cell lymphoma. (13.3%) with rare QTc prolongation and no deaths. Results: The recommended phase II dose was 45 mg/m2 twice Conclusions: The pan-HDACi, abexinostat, was overall well daily (90 mg/m2 total), 7 days/week given every other week. Of tolerated and had significant clinical activity in follicular lym- the 30 follicular lymphoma and mantle cell lymphoma patients phoma, including highly durable responses in this multiply enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell relapsed patient population. Clin Cancer Res; 22(5); 1059–66. lymphoma) were response-evaluable. Tumor size was reduced in Ó2015 AACR. Introduction HDAC inhibitors (HDACi) promote an open chromatin structure by allowing the continued presence of acetyl groups resulting in Epigenetic modulation by histone deacetylation plays a critical transcription of relevant tumor suppressor genes that may favor regulatory role in normal cell processes and has been implicated apoptosis. Clinically, inhibition of HDAC has shown promise for in cancer development and progression (1, 2). Histone deacety- the treatment of B-cell (3) and T-cell lymphomas (4). The HDAC lases (HDAC) and histone acetylases can be aberrantly expressed inhibitors vorinostat, romidepsin, and belinostat are FDA- or deregulated in malignant tissues, resulting in inhibition of approved in cutaneous T-cell lymphoma (CTCL), CTCL and certain tumor suppressor genes and development of malignancy. peripheral T-cell lymphoma (PTCL), and PTCL, respectively (5, 6). There remains an unmet need for additional targeted 1Division of Hematology/Oncology, Tufts Medical Center, Boston, therapeutic options for the treatment of patients with relapsed/ Massachusetts. 2Pharmacyclics, Sunnyvale, California. 3University of refractory B- and T-cell lymphomas. Nebraska Medical Center, Omaha, Nebraska. 4Horizon Oncology Cen- The novel HDACi abexinostat is an oral broad-spectrum phenyl ter, Lafayette, Indiana. 5Northwestern University Feinberg School of Medicine, Chicago, Illinois. 6Nebraska Methodist Hospital, Omaha, hydroxamic acid-based compound being evaluated in the treat- Nebraska. 7Department of Medicine, Vermont Cancer Center, Univer- ment of neoplastic diseases. Abexinostat treatment of non-Hodg- sity of Vermont, Burlington, Vermont. 8Washington University School kin lymphoma (NHL) cell lines (7) resulted in dose-dependent of Medicine, St. Louis, Missouri. apoptosis, G0–G1 arrest, and decreased S-phase and increased p21 Note: Supplementary data for this article are available at Clinical Cancer protein expression. Abexinostat-induced cell death occurred Research Online (http://clincancerres.aacrjournals.org/). through caspase-8 and the Fas-associated death domain, and was Prior Presentation: Presented in abstract form at the 54th annual meeting of the associated with a prominent increase in reactive oxygen species American Society of Hematology (ASH), Atlanta, GA, December 9, 2012. Full and (8). Similar apoptotic responses were observed in neuroblastoma fi nal data presented at the 12th International Conference on Malignant Lym- and soft tissue sarcoma models (9–11). Abexinostat also affects phoma (ICML), Lugano, Switzerland, June 21, 2013. recombination by reducing RAD51, a recA homolog that binds Corresponding Author: Andrew M. Evens, Tufts Medical Center, 800 Washing- single-stranded DNA-forming nucleoprotein filaments essential ton Street, Boston, MA 02111. Phone: 617-636-6227; Fax: 617-636-7060; E-mail: for recombination repair (12, 13). [email protected] Based in part on these preclinical findings, a phase I/II clinical doi: 10.1158/1078-0432.CCR-15-0624 trial was initiated with abexinostat in patients with relapsed/ Ó2015 American Association for Cancer Research. refractory lymphoma. The phase I study examined safety, www.aacrjournals.org 1059 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst October 19, 2015; DOI: 10.1158/1078-0432.CCR-15-0624 Evens et al. after DLT assessment of patients at the end of cycle 1. Dose Translational Relevance escalation followed a 3 þ 3 principle. Inhibition of histone deacytelases (HDAC) has emerged Phase I and phase II enrolled different patients and responders as a promising therapeutic strategy in hematologic malig- who completed treatment were eligible to enroll in a separate nancies. Abexinostat is a novel, oral, broad-spectrum phenyl long-term extension study. In the efficacy evaluation phase hydroxamic acid–based HDAC inhibitor that has demon- (phase II), dosing was based on MTD results from the initial strated preclinical activity in lymphoma cell lines and ani- dose escalation phase and included patients with relapsed/refrac- mal models. This phase I/II study established the appropri- tory follicular lymphoma and mantle cell lymphoma based on ate dose and schedule for use in patients with relapsed/ phase I efficacy signals and historical data with other HDAC refractory non-Hodgkin lymphoma. An intermittent dosing inhibitors. In phase II, the primary end point was overall response schedule was used to achieve good tolerability even during rate (ORR) as defined by disease-specific criteria. Secondary end prolonged drug administration. Incidence of high grade points included duration of response (DOR); time to PD; pro- hematologic adverse events and cardiac toxicities were gression-free survival (PFS); and safety and tolerability. Refractory modest and comparatively encouraging among established disease was defined as no response to prior therapy or relapse agents of this class. In addition, abexinostat was particu- within 3 months of completing prior therapy. larly efficacious in relapsed/refractory follicular lymphoma with prolonged tumor control 18 months in most respon- Patients ders. Further evaluation of this agent as a single-agent Women and men aged 18 years with measurable, histolog- therapy and in combination is warranted and underway ically confirmed, previously treated lymphoma were included. in several tumor types. Phase I included patients with any lymphoma subtype; phase II included patients with follicular lymphoma or mantle cell lym- phoma. Patient requirements for both phases included receipt of prior therapies, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1, adequate organ function, and pharmacokinetics, and pharmacodynamics of different abexino- estimated life expectancy of >12 weeks. Patients were excluded stat treatment schedules in multiple lymphoma subtypes. Fol- from the study if they had platelets <75,000/mL (phase I) and fi lowing identi cation of the appropriate dosing schedule, and <100,000/mL (phase II) or if they had an absolute neutrophil fi based on early ef cacy signals, a phase II extension component count <1,500/mL. was completed in patients with relapsed/refractory follicular Patients were excluded if they had received prior HDACi (unless lymphoma and mantle cell lymphoma. for treatment of mycosis fungoides or Sezary syndrome); allogeneic bone marrow transplantation; immunotherapy, chemotherapy, Materials and Methods radiotherapy, or experimental therapy within 4 weeks before first Study design study dose. Patients were also excluded for primary central nervous This phase I/II study (NCT00724984) was conducted at seven system lymphoma or a history of meningeal carcinomatosis. centers across the United States in accordance with Good Clinical Practice guidelines, as provided by the International Conference Pharmacokinetic analyses on Harmonisation and principles of the Declaration of Helsinki. Plasma concentrations of abexinostat were determined by The institutional review board at each site approved the study. All high-performance liquid chromatography (HPLC) with tandem
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