Randomized, Double-blind Trial of F14512, a Polyamine-vectorized Anticancer Drug, Compared with Etoposide Phosphate, in Dogs with Naturally Occurring Lymphoma

Overview

Journal Oncotarget

Specialty Oncology

Date 2020 Mar 6

PMID 32133044

Citations 2

Authors

Pierre Boye

Franck Floch

Francois Serres

Zacharie Segaoula

Juliette Hordeaux

Quentin Pascal

Virginie Coste

Sandy Courapied

Emmanuel Bouchaert

Agata Rybicka

Claire Mazuy

Laurent Marescaux

Kevyn Geeraert

Corinne Fournel-Fleury

Alain Duhamel

Francois Machuron

Pierre Ferre

Aurelie Petain

Nicolas Guilbaud

Dominique Tierny

Bruno Gomes

Affiliations

Soon will be listed here.

Abstract

F14512 is an epipodophyllotoxin derivative from etoposide, combined with a spermine moiety introduced as a cell delivery vector. The objective of this study was to compare the safety and antitumor activity of F14512 and etoposide phosphate in dogs with spontaneous non-Hodgkin lymphoma (NHL) and to investigate the potential benefit of F14512 in P-glycoprotein (Pgp) overexpressing lymphomas. Forty-eight client-owned dogs with intermediate to high-grade NHL were enrolled into a randomized, double-blind trial of F14512 etoposide phosphate. Endpoints included safety and therapeutic efficacy. Twenty-five dogs were randomized to receive F14512 and 23 dogs to receive etoposide phosphate. All adverse events (AEs) were reversible, and no treatment-related death was reported. Hematologic AEs were more severe with F14512 and gastrointestinal AEs were more frequent with etoposide phosphate. F14512 exhibited similar response rate and progression-free survival (PFS) as etoposide phosphate in the global treated population. Subgroup analysis of dogs with Pgp-overexpressing NHL showed a significant improvement in PFS in dogs treated with F14512 compared with etoposide phosphate. F14512 showed strong therapeutic efficacy against spontaneous NHL and exhibited a clinical benefice in Pgp-overexpressing lymphoma superior to etoposide phosphate. The results clearly justify the evaluation of F14512 in human clinical trials.

Citing Articles

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References

Zandvliet M, Teske E, Schrickx J . Multi-drug resistance in a canine lymphoid cell line due to increased P-glycoprotein expression, a potential model for drug-resistant canine lymphoma. Toxicol In Vitro. 2014; 28(8):1498-506. DOI: 10.1016/j.tiv.2014.06.004. View

Marconato L, Martini V, Aresu L, Sampaolo M, Valentini F, Rinaldi V . Assessment of bone marrow infiltration diagnosed by flow cytometry in canine large B cell lymphoma: prognostic significance and proposal of a cut-off value. Vet J. 2013; 197(3):776-81. DOI: 10.1016/j.tvjl.2013.05.003. View

Sedelnikova O, Bonner W . GammaH2AX in cancer cells: a potential biomarker for cancer diagnostics, prediction and recurrence. Cell Cycle. 2006; 5(24):2909-13. DOI: 10.4161/cc.5.24.3569. View

Hallek M, Langenmayer I, Nerl C, Knauf W, Dietzfelbinger H, Adorf D . Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood. 1999; 93(5):1732-7. View

Gottesman M, Fojo T, Bates S . Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002; 2(1):48-58. DOI: 10.1038/nrc706. View

Kuo L, Yang L . Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo. 2008; 22(3):305-9. View

Lori J, Stein T, Thamm D . Doxorubicin and cyclophosphamide for the treatment of canine lymphoma: a randomized, placebo-controlled study. Vet Comp Oncol. 2010; 8(3):188-95. PMC: 3129606. DOI: 10.1111/j.1476-5829.2010.00215.x. View

LeBlanc A, Breen M, Choyke P, Dewhirst M, Fan T, Gustafson D . Perspectives from man's best friend: National Academy of Medicine's Workshop on Comparative Oncology. Sci Transl Med. 2016; 8(324):324ps5. PMC: 7780241. DOI: 10.1126/scitranslmed.aaf0746. View

Higginbotham M, McCaw D, Roush J, Nietfeld J, Wilkerson M, Reeds K . Intermittent single-agent doxorubicin for the treatment of canine B-cell lymphoma. J Am Anim Hosp Assoc. 2013; 49(6):357-62. DOI: 10.5326/JAAHA-MS-5929. View

10.

Ponce F, Marchal T, Magnol J, Turinelli V, Ledieu D, Bonnefont C . A morphological study of 608 cases of canine malignant lymphoma in France with a focus on comparative similarities between canine and human lymphoma morphology. Vet Pathol. 2010; 47(3):414-33. DOI: 10.1177/0300985810363902. View

11.

Ito D, Frantz A, Modiano J . Canine lymphoma as a comparative model for human non-Hodgkin lymphoma: recent progress and applications. Vet Immunol Immunopathol. 2014; 159(3-4):192-201. PMC: 4994713. DOI: 10.1016/j.vetimm.2014.02.016. View

12.

Lynch S, Savary-Bataille K, Leeuw B, Argyle D . Development of a questionnaire assessing health-related quality-of-life in dogs and cats with cancer. Vet Comp Oncol. 2011; 9(3):172-82. DOI: 10.1111/j.1476-5829.2010.00244.x. View

13.

Fournel-Fleury C, Magnol J, Bricaire P, Marchal T, Chabanne L, Delverdier A . Cytohistological and immunological classification of canine malignant lymphomas: comparison with human non-Hodgkin's lymphomas. J Comp Pathol. 1997; 117(1):35-59. DOI: 10.1016/s0021-9975(97)80065-5. View

14.

Sokolowska J, Urbanska K, Gizinski S, Zabielska K, Lechowski R . Immunohistochemical detection of P-glycoprotein in various subtypes of canine lymphomas. Pol J Vet Sci. 2015; 18(1):123-30. DOI: 10.1515/pjvs-2015-0016. View

15.

Mouawad F, Gros A, Rysman B, Bal-Mahieu C, Bertheau C, Horn S . The antitumor drug F14512 enhances cisplatin and ionizing radiation effects in head and neck squamous carcinoma cell lines. Oral Oncol. 2013; 50(2):113-9. DOI: 10.1016/j.oraloncology.2013.11.003. View

16.

Vajdovich P, Koltai Z, Dekay V, Kungl K, Harnos A . Evaluation of Pgp (MDR1) immunohistochemistry in canine lymphoma - prognostic and clinical aspects. Acta Vet Hung. 2018; 66(2):309-328. DOI: 10.1556/004.2018.028. View

17.

Siderov J, Prasad P, de Boer R, Desai J . Safe administration of etoposide phosphate after hypersensitivity reaction to intravenous etoposide. Br J Cancer. 2002; 86(1):12-3. PMC: 2746527. DOI: 10.1038/sj.bjc.6600003. View

18.

Gentry A, Pitts S, Jablonsky M, Bailly C, Graves D, Osheroff N . Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme-mediated DNA cleavage. Biochemistry. 2011; 50(15):3240-9. PMC: 3086367. DOI: 10.1021/bi200094z. View

19.

Kruczynski A, Vandenberghe I, Pillon A, Pesnel S, Goetsch L, Barret J . Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system. Invest New Drugs. 2009; 29(1):9-21. DOI: 10.1007/s10637-009-9328-3. View

20.

ONeill K, Buckwalter M, Murray B . Thymidine kinase: diagnostic and prognostic potential. Expert Rev Mol Diagn. 2002; 1(4):428-33. DOI: 10.1586/14737159.1.4.428. View