A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma

Andrew M. Evens, Sriram Balasubramanian, Julie Marie Vose, Wael Harb, Leo I. Gordon, Robert Langdon, Julian Sprague, Mint Sirisawad, Chitra Mani, Jeanne Yue, Ying Luan, Sharon Horton, Thorsten Graef, Nancy L. Bartlett

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Abstract

Purpose: 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.Weconducted amulticenter phase I/II study (N=55)with single-agent abexinostat in relapsed/refractory lymphoma. Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m2 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/m2 twice daily (90 mg/m2 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 investigatorassessed 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.

Original languageEnglish (US)
Pages (from-to)1059-1066
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2016

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Histone Deacetylase Inhibitors
Follicular Lymphoma
Lymphoma
Mantle-Cell Lymphoma
Disease-Free Survival
Maximum Tolerated Dose
abexinostat
Neutropenia
Thrombocytopenia
Fatigue
Research Design
Therapeutics
Incidence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma. / Evens, Andrew M.; Balasubramanian, Sriram; Vose, Julie Marie; Harb, Wael; Gordon, Leo I.; Langdon, Robert; Sprague, Julian; Sirisawad, Mint; Mani, Chitra; Yue, Jeanne; Luan, Ying; Horton, Sharon; Graef, Thorsten; Bartlett, Nancy L.

In: Clinical Cancer Research, Vol. 22, No. 5, 01.03.2016, p. 1059-1066.

Research output: Contribution to journalArticle

Evens, AM, Balasubramanian, S, Vose, JM, Harb, W, Gordon, LI, Langdon, R, Sprague, J, Sirisawad, M, Mani, C, Yue, J, Luan, Y, Horton, S, Graef, T & Bartlett, NL 2016, 'A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma', Clinical Cancer Research, vol. 22, no. 5, pp. 1059-1066. https://doi.org/10.1158/1078-0432.CCR-15-0624
Evens, Andrew M. ; Balasubramanian, Sriram ; Vose, Julie Marie ; Harb, Wael ; Gordon, Leo I. ; Langdon, Robert ; Sprague, Julian ; Sirisawad, Mint ; Mani, Chitra ; Yue, Jeanne ; Luan, Ying ; Horton, Sharon ; Graef, Thorsten ; Bartlett, Nancy L. / A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 5. pp. 1059-1066.
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abstract = "Purpose: 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.Weconducted amulticenter phase I/II study (N=55)with single-agent abexinostat in relapsed/refractory lymphoma. Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m2 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/m2 twice daily (90 mg/m2 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 investigatorassessed 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.",
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AU - Evens, Andrew M.

AU - Balasubramanian, Sriram

AU - Vose, Julie Marie

AU - Harb, Wael

AU - Gordon, Leo I.

AU - Langdon, Robert

AU - Sprague, Julian

AU - Sirisawad, Mint

AU - Mani, Chitra

AU - Yue, Jeanne

AU - Luan, Ying

AU - Horton, Sharon

AU - Graef, Thorsten

AU - Bartlett, Nancy L.

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N2 - Purpose: 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.Weconducted amulticenter phase I/II study (N=55)with single-agent abexinostat in relapsed/refractory lymphoma. Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m2 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/m2 twice daily (90 mg/m2 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 investigatorassessed 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.

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