Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors

Shuang Cai, Ti Zhang, W. C. Forrest, Qiuhong Yang, Chad Groer, Eva Mohr, Daniel J. Aires, Sandra M. Axiak-Bechtel, Brian K. Flesner, Carolyn J. Henry, Kimberly A. Selting, Deborah Tate, Jeffrey A. Swarz, Jeffrey N. Bryan, M. Laird Forrest

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Abstract

OBJECTIVE To conduct a phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate (HA-Pt) in dogs with naturally occurring malignant tumors. ANIMALS 18 healthy rats, 9 healthy mice, and 16 dogs with cancer. PROCEDURES HA-Pt was prepared and tested by inductively coupled plasma mass spec­trometry; DNA-platinum adduct formation and antiproliferation effects of cisplatin and HA-Pt were compared in vitro. Effects of cisplatin (IV) and HA-Pt (SC) in rodents were tested by clinicopathologic assays. In the clinical trial, dogs with cancer received 1 to 4 injections of HA-Pt (10 to 30 mg/m2, intratumoral or peritumoral, q 3 wk). Blood samples were collected for phar­macokinetic analysis; CBC, serum BUN and creatinine concentration measure­ment, and urinalysis were conducted before and 1 week after each treatment. Some dogs underwent hepatic enzyme testing. Tumors were measured before the first treatment and 3 weeks after each treatment to assess response. RESULTS No adverse drug effects were detected in pretrial assessments in rodents. Seven of 16 dogs completed the study; 3 had complete tumor responses, 3 had stable disease, and 1 had progressive disease. Three of 7 dogs with oral and nasal squamous cell carcinoma (SCC) that completed the study had complete responses. Myelosuppression and cardiotoxicosis were iden­tified in 6 and 2 dogs, respectively; none had nephrotoxicosis. Four of 5 dogs with hepatic enzymes assessed had increased ALT activities, attributed to diaquated cisplatin products in the HA-Pt. Pharmacokinetic data fit a 3-compartment model. CONCLUSIONS AND CLINICAL RELEVANCE HA-Pt treatment resulted in positive tumor responses in some dogs, pri­marily those with SCC. The adverse effect rate was high. IMPACT FOR HUMAN MEDICINE Oral SCC in dogs has characteristics similar to human head and neck SCC; these results could be useful in developing human treatments.

Original languageEnglish (US)
Pages (from-to)1005-1016
Number of pages12
JournalAmerican journal of veterinary research
Volume77
Issue number9
DOIs
StatePublished - Sep 2016

ASJC Scopus subject areas

  • veterinary(all)

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    Cai, S., Zhang, T., Forrest, W. C., Yang, Q., Groer, C., Mohr, E., Aires, D. J., Axiak-Bechtel, S. M., Flesner, B. K., Henry, C. J., Selting, K. A., Tate, D., Swarz, J. A., Bryan, J. N., & Forrest, M. L. (2016). Phase I-II clinical trial of hyaluronan-cisplatin nanoconjugate in dogs with naturally occurring malignant tumors. American journal of veterinary research, 77(9), 1005-1016. https://doi.org/10.2460/ajvr.77.9.1005