An Open‐label Phase 1 Dose‐escalation Clinical Trial of a Single Intravenous Administration of Gemcitabine in Dogs with Advanced Solid Tumors

Abstract

BackgroundA broad range of gemcitabine dosages have been used in dogs.Hypothesis/ObjectivesTo determine maximally tolerated dose (MTD), dose‐limiting toxicity (DLT), and preliminary antitumor activity of intravenous administration of gemcitabine in dogs with advanced solid tumors.AnimalsTwenty‐two client‐owned dogs.MethodsDogs with advanced cancer were prospectively enrolled in an open‐label Phase 1 study of gemcitabine. Gemcitabine was administered as a 30‐minute intravenous bolus starting at 800 mg/m2, using escalation of 50 mg/m2 increments with 3 dogs per dose level. MTD was established based on the number of dogs experiencing DLT assessed after 1 cycle. Treatment continued until disease progression or unacceptable toxicosis. Additional dogs were enrolled at MTD to better characterize tolerability, and to assess the extent and duration of gemcitabine excretion.ResultsTwenty‐two dogs were treated at 4 dose levels, ranging from 800 to 950 mg/m2. Neutropenia was identified as DLT. MTD was 900 mg/m2. DLT consisting of grade 4 febrile neutropenia was observed at 950 mg/m2 in 2 dogs. There were no nonhematologic DLTs. Twenty dogs received multiple doses, and none had evidence of severe toxicosis from any of their subsequent treatments. At 900 mg/m2, 2 complete and 5 partial responses were observed in dogs with measurable tumors. The amount of gemcitabine excreted in urine decreased over time, and was undetectable after the first 24 hours.Conclusions and Clinical ImportanceThe recommended dose of gemcitabine for future Phase 2 studies is weekly 900 mg/m2. In chemotherapy‐naïve dogs with advanced solid tumor this dose level merits further evaluation.

Palliative care in small animal oncology

“…Additional modifications can be made as necessary in patients in which toxicity is a problem so that quality of life is maintained during treatment. Chemotherapy can be used before (neoadjunctive) or after (adjunctive) surgery for solid tumours and occasionally as a sole agent in the palliative setting (Page and others 1993, Chun and others 1997, Bacon and others 2008, Bailey and others 2008, Bulakowski and others 2008, Grant and others 2008, Kisseberth and others 2008, Rassnick and others 2008, Cooper and others 2009, Dominguez and others 2009, Lori and others 2010, Arnold and others 2011, Fidel and others 2011, Bray and Polton 2014, Selmic and others 2014, Cannon and others 2015, Culp and others 2015, Marconato and others 2015) (Table 5). Intracavitatory chemotherapy can be useful in some patients with neoplastic pleural effusion (Charney and others 2005); permanent pleural ports are well tolerated and facilitate delivery as well as allowing drainage of the effusion.…”

Drug dose and drug choice: Optimizing medical therapy for veterinary cancer

“…Conventional phase‐I clinical trials in tumor‐bearing dogs, designed to optimize dosing in small cohorts of patients, have demonstrated associations between higher dose and increased response rates . However, it is likely that careful dose escalation beyond the “established” maximum tolerated dose may be tolerable and potentially associated with improvements in outcome in certain patients.…”