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Safety Evaluation of Combination Doxorubicin and Toceranib Phosphate (Palladia®) in Tumour Bearing Dogs: a Phase I Dose-finding Study

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Safety Evaluation of Combination Doxorubicin and Toceranib Phosphate (Palladia®) in Tumour Bearing Dogs: a Phase I Dose-finding Study Original Article DOI: 10.1111/vco.12232 Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose-finding study M. A. Pellin1,∗,R.M.Wouda2,∗,K.Robinson1,K.Tsimbas1,I.D.Kurzman1, B. J. Biller3 andD.M.Vail1,4 1Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA 2Kansas State University, College of Veterinary Medicine, Manhattan, KS, USA 3Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, USA 4Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA Abstract Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single-agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose-finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg−1 by mouth every other day (PO EOD) while escalating DOX dosage. The dose-limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m−2 of DOX q 21 days given concurrently Keywords with toceranib 2.75 mg kg−1 PO EOD. This combination was well tolerated with no excessive cancer, canine, gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti-tumour activity was observed in chemotherapy, doxorubicin, toceranib, the majority of cases. This combination warrants further investigation in the context of phase II/III Tregs clinical trials to characterize efficacy and long-term AE profiles. Introduction proven single-agent activity against the tumour A seminal discovery in the evolution of cancer histotype being treated. The antitumour mech- treatment was the advantage of combination anism for each of the drugs should differ and, chemotherapy regimens over single-agent ther- related to this, drugs with considerably similar apy. There now exists ample clinical precedent adverse event (AE) profiles should be avoided. Correspondence address for the use of multi-agent protocols, and almost Finally, the drugs should be able to be administered D. M. Vail School of Veterinary all curative-intent protocols in human oncology at their optimal therapeutic dose and interval. Medicine incorporate a minimum of two or three chemother- Mindful of these criteria, our group has previously University of apeutic agents with additive or synergistic activity. evaluated the combinations of toceranib phos- Wisconsin-Madison ® 2015 Linden Dr. Ideally, such combination chemotherapy protocols phate (Palladia ) with piroxicam, vinblastine, and Madison adhere to several principles, in order to optimize CCNU (lomustine) in dogs.2–5 Further inves- WI 53706 clinical benefit.1 The individual drugs should have tigations of multi-drug chemotherapy protocols USA e-mail: are warranted in veterinary oncology to strive for [email protected] ∗ These authors contributed equally to this work. increased efficacy and improved outcomes in our © 2016 John Wiley & Sons Ltd 919 920 M. A. Pellin et al. companion animals with spontaneously arising are also seen in humans secondary to RTKI use. tumours. The mechanisms of these toxicities have not been Doxorubicin (DOX) is an anthracycline derived determined but are suggested to occur secondary to from Streptomyces yeast species.6 It has multiple inhibition of VEGF.14 Less frequent toxicities that mechanisms of cellular toxicity, including interca- have been reported in dogs include musculoskele- lation of DNA leading to inhibition of protein syn- tal pain, elevated liver enzymes and azotemia. thesis, free radical formation and topoisomerase Haematopoietic toxicity is uncommonly reported enzyme inhibition. DOX is one of the most com- withtoceranibandistypicallymildifitisnoted monly utilized chemotherapy agents in veterinary at all. Cardiotoxicity including left ventricular medicine and has showed activity against a vari- dysfunction, congestive heart failure and throm- ety of histologies.6,7 This broad spectrum of activ- boembolic disease, is also uncommonly reported ity makes DOX an attractive agent to combine with secondary to RTKI use in human patients.14 To other agents to further enhance antitumour activ- the authors’ knowledge, these effects have not ity. The AE profile of single-agent DOX in dogs is been commonly reported in canine patients. The well established with myelosuppression, in particu- complexity of the RTKIs’ cellular interactions is not lar neutropenia, being the acute dose-limiting AE yet completely appreciated and there is ongoing and myocardial toxicity with cumulative doses over research interrogating the potential roles of the 180–240 mg m−2 being the chronic dose-limiting receptor RTKIs as chemosensitizers, radiation AE.6,8 Other AEs common following DOX include sensitizers, immune modulators and in reversing alopecia and gastrointestinal AEs such as vomit- acquired chemotherapy resistance. Toceranib has ing and diarrhoea, with the latter occasionally being alsobeenshowninonestudytoresultinselective dose-limiting. depletion of circulating regulatory T lymphocytes Toceranib phosphate (Palladia; Zoetis, Florham (Tregs)intumour-bearingdogswhenusedasa Park, NJ) is a receptor tyrosine kinase inhibitor single agent and when combined with metronomic (RTKI) possessing inhibitory activity against cyclophosphamide.15 several members of the receptor tyrosine kinase The hypothesis under investigation in this trial family of transmembrane proteins, including the wasthattoceranibcouldbesafelyadministeredto cell surface receptors for vascular endothelial dogs with naturally occurring malignancies on an growth factor (VEGF), platelet-derived growth every other day (EOD) schedule in combination factor (PDGF), stem cell factor (SCF), cytokine withDOXadministeredevery3weeks,atdosages Flt-3 ligand, and the GDNF-family ligands.9,10 with respective demonstrable single-agent activity. Toceranib’s activity results from competitive block- This study had three objectives. The primary objec- adeoftheATP-bindingsiteofthesetyrosinekinase tive was to employ a conventional 3 + 3phaseI receptors, resulting in impaired phosphorylation study design to determine the maximum tolerated and diminished down-stream signalling.11 In a dose (MTD) of DOX that can be safely admin- phase I dose-finding study of toceranib, clinical istered to tumour-bearing dogs with concurrent responses were observed in a variety of tumour toceranib administered according to a standard types including metastatic carcinomas, sarcomas, dose and schedule.16 The second objective was to multiple myeloma and melanoma.10 Subsequent characterize the AE profile of combination DOX off-label investigation further supported a role for and toceranib in dogs. A third objective was to toceranib in the treatment of numerous canine characterize the effect of the DOX/toceranib com- neoplasms, including osteosarcoma, thyroid car- bination protocol on circulating Tregs owing to cinoma, apocrine gland anal sac adenocarcinoma, toceranib’s previously documented immunomod- nasal carcinoma and head and neck squamous cell ulatory single-agent effect on this lymphocyte carcinomas.12 Toceranib’s most common AEs are subpopulation. Whilst efficacy is never a primary gastrointestinal, especially diarrhoea.10,13 Protein- endpoint of such dose-finding studies, clinical uriaandhypertensionarealsocommonlyseen benefit was also evaluated throughout the study secondary to toceranib use in our institution, and period. © 2016 John Wiley & Sons Ltd, Veterinary and Comparative Oncology, 15, 3, 919–931 Safety of concurrent doxorubicin and toceranib combination therapy 921 Methods the DOX dose increasing with each cohort and the toceranib dose remaining constant. The ini- Patient selection tial cohort received DOX at a dose of 20 mg m−2 Client-owned dogs with one or more cytologically administered intravenously (IV) every 21 days for a and/or histologically diagnosed malignant tumours total of four doses. DOX was escalated by 5 mgm−2 of any histology (excluding mast cell tumours), foreachcohortuntilMTDorthestandarddoseof gradeandstagewereconsideredforenrollment. 30 mg m−2 was reached, whichever came first. The Dogs with mast cell tumours were excluded given toceranib dose was maintained at approximately the investigators’ concern regarding the paraneo- 2.75 mg kg−1 by mouth (PO) EOD throughout the plastic gastrointestinal effects observed with this trial period and extending for a minimum of 7 days histology, which could confound interpretation following the fourth DOX dose. Toceranib dosing of gastrointestinal AEs secondary to proposed was necessarily approximate to accommodate the therapy, especially in this smaller study population. drug’s commercially available tablet sizes. Owners Prior surgery was allowed, hence, measurable were given the option of having their dog receive macroscopic disease was not an inclusion criteria. a fifth dose of DOX and/or continuing toceranib Prior radiation therapy, chemotherapy (other than after trial conclusion. DOX or toceranib) and corticosteroid therapy Three dogs were enrolled in each cohort and were also allowed, with adherence to the prede- then observed for dose-limiting toxicities (DLTs). termined minimum washout periods of 3 weeks ADLTwasdefinedasanygrade3orhigherAE for both radiation and chemotherapy, and 72 h for (VCOG-CTCAE v1.117) with the exception of corticosteroid
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