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

Shuang Cai Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66049.
HylaPharm LLC, 2029 Becker Dr, Lawrence, KS 66047.

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Ti Zhang Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66049.
HylaPharm LLC, 2029 Becker Dr, Lawrence, KS 66047.

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W.C. Forrest HylaPharm LLC, 2029 Becker Dr, Lawrence, KS 66047.

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Qiuhong Yang Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66049.

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Chad Groer HylaPharm LLC, 2029 Becker Dr, Lawrence, KS 66047.

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Eva Mohr HylaPharm LLC, 2029 Becker Dr, Lawrence, KS 66047.

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Daniel J. Aires HylaPharm LLC, 2029 Becker Dr, Lawrence, KS 66047.
University of Kansas Medical Center, Kansas City, KS 66160.

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Sandra M. Axiak-Bechtel Department of Oncology, University of Missouri, Columbia, MO 65211.

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Brian K. Flesner Department of Oncology, University of Missouri, Columbia, MO 65211.

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Carolyn J. Henry Department of Oncology, University of Missouri, Columbia, MO 65211.

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Kimberly A. Selting Department of Oncology, University of Missouri, Columbia, MO 65211.

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Deborah Tate Department of Oncology, University of Missouri, Columbia, MO 65211.

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Jeffrey A. Swarz Department of Oncology, University of Missouri, Columbia, MO 65211.

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Jeffrey N. Bryan Department of Oncology, University of Missouri, Columbia, MO 65211.

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M. Laird Forrest Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66049.
HylaPharm LLC, 2029 Becker Dr, Lawrence, KS 66047.

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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.

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.

Contributor Notes

Address correspondence to Dr. M. L. Forrest (lforrest@ku.edu).
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