Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma

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Abstract

Background

Chemotherapeutic options for the treatment of canine lymphoma have not changed in several decades necessitating the identification of new therapeutics to improve patient outcome. KPT-335 (verdinexor) is a novel orally bioavailable selective inhibitor of nuclear export (SINE) that exhibited anti-tumor activity against non-Hodgkin lymphoma in a prior phase I study. The objective of this phase II study was to expand upon the initial findings and assess the activity and safety in a larger population of dogs with lymphoma.

Results

Fifty-eight dogs with naïve or progressive B-cell and T-cell lymphoma were enrolled in this clinical trial. KPT-335 was administered orally in one of three dosing groups, based on the previously established biologically active dose of 1.5 mg/kg three times weekly. Treatment with single-agent, orally administered KPT-335 resulted in an objective response rate (ORR) of 37%, of which dogs with T-cell lymphoma had an ORR of 71%. KPT-335 was well tolerated in all dose groups with grade 1–2 anorexia being the most common adverse event. Anorexia was responsive to symptomatic and supportive medications, including prednisone.

Conclusions

These data demonstrate that KPT-335 has biologic activity in canine lymphoma, and support continued evaluation of SINE compounds such as KPT-335 in combination with standard chemotherapeutics in canine lymphoma.

Electronic supplementary material

The online version of this article (10.1186/s12917-018-1587-9) contains supplementary material, which is available to authorized users.

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Most cited references 16

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Nuclear export of proteins and drug resistance in cancer.

Joel Turner, Jana Dawson, Daniel Sullivan (2012)

The intracellular location of a protein is crucial to its normal functioning in a cell. Cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of a cell to effectively evade anti-neoplastic mechanisms. CRM1-mediated export is increased in various cancers. Proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, APC, p53, BRAC1, FOXO proteins, INI1/hSNF5, galectin-3, Bok, nucleophosmin, RASSF2, Merlin, p21(CIP), p27(KIP1), N-WASP/FAK, estradiol receptor and Tob, drug targets topoisomerase I and IIα and BCR-ABL, and the molecular chaperone protein Hsp90. Here, we review in detail the current processes and known structures involved in the export of a protein through the nuclear pore complex. We also discuss the export receptor molecule CRM1 and its binding to the leucine-rich nuclear export signal of the cargo protein and the formation of a nuclear export trimer with RanGTP. The therapeutic potential of various CRM1 inhibitors will be addressed, including leptomycin B, ratjadone, KOS-2464, and specific small molecule inhibitors of CRM1, N-azolylacrylate analogs, FOXO export inhibitors, valtrate, acetoxychavicol acetate, CBS9106, and SINE inhibitors. We will also discuss examples of how drug resistance may be reversed by targeting the exported proteins topoisomerase IIα, BCR-ABL, and galectin-3. As effective and less toxic CRM1 export inhibitors become available, they may be used as both single agents and in combination with current chemotherapeutic drugs. We believe that the future development of low-toxicity, small-molecule CRM1 inhibitors may provide a new approach to treating cancer. Copyright Â© 2011 Elsevier Inc. All rights reserved.

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Nucleo-cytoplasmic transport as a therapeutic target of cancer

Giovanni Gravina, William Senapedis, Dilara McCauley … (2014)

Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer.

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First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors.

Albiruni Abdul Razak, Morten Mau-Soerensen, Nashat Y Gabrail … (2016)

Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m(2)) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m(2) using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m(2) given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m(2) before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for ≥ 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted.

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Author and article information

Contributors

Cheryl A. London:

ORCID: http://orcid.org/0000-0001-8563-1490

614-915-7409 , Cheryl.London@tufts.edu

Journal

Journal ID (nlm-ta): BMC Vet Res

Journal ID (iso-abbrev): BMC Vet. Res

Title: BMC Veterinary Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1746-6148

Publication date (Electronic): 24 August 2018

Publication date PMC-release: 24 August 2018

Publication date Collection: 2018

Volume: 14

Electronic Location Identifier: 250

Affiliations

[1 ]ISNI 0000 0004 1936 7531, GRID grid.429997.8, Cummings School, Tufts University, Foster Hospital for Small Animals, ; 200 Westboro Rd, N. Grafton, MA 01536 USA

[2 ]ISNI 0000 0004 1936 7531, GRID grid.429997.8, Sackler School of Graduate Biomedical Sciences, , Tufts University, ; Boston, MA USA

[3 ]ISNI 0000000419368657, GRID grid.17635.36, College of Veterinary Medicine, , University of Minnesota, ; St. Paul, MN USA

[4 ]ISNI 0000 0004 4687 2082, GRID grid.264756.4, College of Veterinary Medicine, , Texas A&M University, ; College Station, TX USA

[5 ]ISNI 0000 0001 2167 3675, GRID grid.14003.36, Department of Medical Sciences, School of Veterinary Medicine, , University of Wisconsin-Madison, ; Madison, WI USA

[6 ]NYC Veterinary Specialists/Blue Pearl Veterinary Specialists, New York, NY USA

[7 ]The Oncology Service, The LifeCentre, Leesburg, VA USA

[8 ]Veterinary Cancer Group, Culver City, CA USA

[9 ]Southern Arizona Veterinary Specialty and Emergency Center, Tucson, AZ USA

[10 ]The Oncology Service, Dogwood Veterinary Emergency and Specialty Center, Richmond, VA USA

[11 ]The Oncology Service, Friendship Hospital for Animals, Washington DC, USA

[12 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Department of Veterinary Biosciences, College of Veterinary Medicine, , The Ohio State University, ; Columbus, OH USA

Author information

Cheryl A. London http://orcid.org/0000-0001-8563-1490

Article

Publisher ID: 1587

DOI: 10.1186/s12917-018-1587-9

PMC ID: 6109271

PubMed ID: 30143046

SO-VID: ed2840be-c275-4867-9c69-d38fdcd34e04

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 May 2018

Date accepted : 20 August 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100007136, Karyopharm Therapeutics;

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ScienceOpen disciplines: Veterinary medicine

Keywords: non-hodgkin lymphoma,nuclear export,clinical trial,anti-tumor agent

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ScienceOpen disciplines: Veterinary medicine

Keywords: non-hodgkin lymphoma, nuclear export, clinical trial, anti-tumor agent

Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma

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Most cited references 16

Nuclear export of proteins and drug resistance in cancer.

Nucleo-cytoplasmic transport as a therapeutic target of cancer

First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors.

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