Pulse-administered toceranib phosphate plus lomustine for treatment of unresectable mast cell tumors in dogs

Jenna H Burton, R. O. Venable, D. M. Vail, L. E. Williams, C. A. Clifford, S. M. Axiak-Bechtel, A. C. Avery, D. H. Thamm

Research output: Contribution to journalArticle

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Abstract

Background: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. Hypothesis/Objectives: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. Animals: Forty-seven client-owned dogs with measurable MCT. Methods: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m2. All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. Results: The MTD of lomustine was established at 50 mg/m2 when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. Conclusions and clinical importance: Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.

Original languageEnglish (US)
Pages (from-to)1098-1104
Number of pages7
JournalJournal of Veterinary Internal Medicine
Volume29
Issue number4
DOIs
StatePublished - 2015

Fingerprint

Lomustine
mast cells
Mast Cells
Dogs
Maximum Tolerated Dose
phosphates
neoplasms
dogs
dosage
Neoplasms
Disease-Free Survival
drug therapy
Therapeutics
Diphenhydramine
Drug Therapy
Omeprazole
prednisone
neutropenia
therapeutics
Prednisone

Keywords

  • Cancer
  • Chemotherapy
  • Dog
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • veterinary(all)

Cite this

Burton, J. H., Venable, R. O., Vail, D. M., Williams, L. E., Clifford, C. A., Axiak-Bechtel, S. M., ... Thamm, D. H. (2015). Pulse-administered toceranib phosphate plus lomustine for treatment of unresectable mast cell tumors in dogs. Journal of Veterinary Internal Medicine, 29(4), 1098-1104. https://doi.org/10.1111/jvim.13573

Pulse-administered toceranib phosphate plus lomustine for treatment of unresectable mast cell tumors in dogs. / Burton, Jenna H; Venable, R. O.; Vail, D. M.; Williams, L. E.; Clifford, C. A.; Axiak-Bechtel, S. M.; Avery, A. C.; Thamm, D. H.

In: Journal of Veterinary Internal Medicine, Vol. 29, No. 4, 2015, p. 1098-1104.

Research output: Contribution to journalArticle

Burton, JH, Venable, RO, Vail, DM, Williams, LE, Clifford, CA, Axiak-Bechtel, SM, Avery, AC & Thamm, DH 2015, 'Pulse-administered toceranib phosphate plus lomustine for treatment of unresectable mast cell tumors in dogs', Journal of Veterinary Internal Medicine, vol. 29, no. 4, pp. 1098-1104. https://doi.org/10.1111/jvim.13573
Burton, Jenna H ; Venable, R. O. ; Vail, D. M. ; Williams, L. E. ; Clifford, C. A. ; Axiak-Bechtel, S. M. ; Avery, A. C. ; Thamm, D. H. / Pulse-administered toceranib phosphate plus lomustine for treatment of unresectable mast cell tumors in dogs. In: Journal of Veterinary Internal Medicine. 2015 ; Vol. 29, No. 4. pp. 1098-1104.
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abstract = "Background: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. Hypothesis/Objectives: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. Animals: Forty-seven client-owned dogs with measurable MCT. Methods: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m2. All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. Results: The MTD of lomustine was established at 50 mg/m2 when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46{\%} (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. Conclusions and clinical importance: Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.",
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AU - Burton, Jenna H

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AU - Williams, L. E.

AU - Clifford, C. A.

AU - Axiak-Bechtel, S. M.

AU - Avery, A. C.

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