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

Abstract

Objective To conduct an open label, multi-dose Phase I/II clinical study in spontaneous canine cancers and evaluate the pharmacokinetics, safety, and efficacy of the hyaluronan-based cisplatin formulation (HA-Pt). Animals 13 dogs with heterogeneous, naturally occurring cancers. Procedures The dogs received up to four injections of 10-30 mg/m2 HA-Pt into the tumor or peritumoral sub-mucosa at three-week intervals. Blood sample (2 mL) was collected from the jugular catheter at 0.5, 1, 2, 4, and 24 hours following drug administration. A complete blood count and renal profile with urinalysis were conducted prior to and one week after each treatment. Tumor measurements were collected three weeks following each administration to assess response. Results Of the 13 dogs with heterogeneous, naturally occurring cancers, 23% had complete response and 15% had partial response or stable disease. Among the dogs that received drug with low diaquated content, the complete response rate for SCC was 3/7 (43%). Myelosuppression and cardiac toxicity were observed for 38% and 19% of the dogs, respectively. The formulation did not cause nephrotoxicity, the dose-limiting toxicity of standard cisplatin, in any dogs. Conclusions and Clinical Relevance The HA-Pt formulation demonstrated positive response in spontaneous canine squamous cell carcinomas. It did not cause nephrotoxicity in any patients. Canine oral SCC is very homogenous in progression and drug response to human HNSCC, and these results could be useful in developing human treatments.

Injectable Chemotherapy Downstaged Oral Squamous Cell Carcinoma from Nonresectable to Resectable in a Rescue Dog: Diagnosis, Treatment, and Outcome

“…In a Phase I pharmacokinetic and short-term tolerability study, HylaPlat has shown satisfactory tolerability and improved distribution along with sustained retention in tumor and draining lymphatics in dogs with spontaneous soft tissue sarcomas [ 2 ]. In a combined Phase I/II study in dogs with naturally occurring malignant oral and nasal SCC, 3 of 7 dogs (43%) that received low-diaqua formulations of HylaPlat demonstrated complete responses [ 3 ]. The newer lyophilized formulation in the present report appears to have improved stability and safety since the medication can be reconstituted in water just prior to administration.…”

“…HylaPlat has improved pharmacokinetics and sustained retention compared to intravenous cisplatin in dogs [ 2 ]. It is effective against oral squamous cell carcinomas in dogs as demonstrated by our previous Phase I/II clinical study [ 3 ] as well as other canine clinical studies in the literature [ 4 , 5 ]. Previously, HylaPlat was formulated as a liquid based injectable that had a short shelf life.…”

“…Because platinum chemotherapy may induce tubular injuries and may cause nephrotoxicity, renal function was monitored by BUN and creatinine tests during the study to assess systemic tolerability [ 3 ]. Test results demonstrated that neither BUN nor creatinine was elevated during the treatment period.…”

The Use of Liposomes and Nanoparticles as Drug Delivery Systems to Improve Cancer Treatment in Dogs and Cats

“…Furthermore, in a phase I clinical trial of sixteen dogs with spontaneous tumours, three dogs reached complete response (two had oral and one nasal planum squamous cell carcinoma) and three dogs had stable disease after intratumoral or peritumoral HA–Pt injections (10–30 mg/m 2 , 1–4 intratumoral or peritumoral injections at 3 week-intervals), which is better than previously reported studies of free cisplatin. Although the toxicity rate for this study was high (60%), the authors explained it as a result of poor compound purification prior to performing the trial, resulting in diaquated impurities [ 54 ]. Interestingly, no nephrotoxicity, the main adverse effect of cisplatin treatment, was noticed in any of the dogs tested.…”

“…This is opposed to liver damage, an extremely rare side effect of standard cisplatin treatment, which resulted following HA–Pt administration. Hepatotoxicity probably appeared due to the large size of polymer-based HA–Pt, which could not be cleared through the kidney, and the HA, which is normally metabolized in the liver, that was used as the DDS [ 54 ]. Based on these primary results, a clinical trial on intratumoral injections of HA–Pt was recently approved for the treatment of mouth cancers (melanoma and sarcoma) in dogs (study No.…”