Safety evaluation of combination <scp>CCNU</scp> and continuous toceranib phosphate (Palladia<sup>®</sup>) in tumour‐bearing dogs: a phase I dose‐finding study

Pan, Xin; Tsimbas, K.; Kurzman, Ilene D.; Vail, David M.

doi:10.1111/vco.12091

Cited by 24 publications

(26 citation statements)

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“…A lomustine MTD of 50 mg/m 2 once every 3 weeks when combined with continuous dosing of TOC at 2.75 mg/ kg every other day recently was reported when administered to dogs with tumors other than MCT; the DLT in this phase I study with continuous TOC administration also was neutropenia. 29 Other common adverse effects included hepatic and gastrointestinal toxicities, which were not unexpected based on the combination of drugs used in this protocol. Lomustine is known to cause hepatotoxicity in dogs, with reported rates of 83-86%.…”

Section: Discussionmentioning

confidence: 93%

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

Burton

Venable

Vail

et al. 2015

Veterinary Internal Medicne

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BackgroundNonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy.Hypothesis/ObjectivesThe primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse‐administered toceranib phosphate (TOC) combined with lomustine.AnimalsForty‐seven client‐owned dogs with measurable MCT.MethodsToceranib phosphate was given PO on days 1, 3 and 5 of a 21‐day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m2. All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone.ResultsThe MTD of lomustine was established at 50 mg/m2 when combined with pulse‐administered TOC; the dose‐limiting toxicity was neutropenia. Forty‐one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression‐free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy.Conclusions and clinical importanceCombined treatment with pulse‐administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.

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Section: Discussionmentioning

confidence: 93%

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

Burton

Venable

Vail

et al. 2015

Veterinary Internal Medicne

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“…Finally, the drugs should be able to be administered at their optimal therapeutic dose and interval. Mindful of these criteria, our group has previously evaluated the combinations of toceranib phosphate (Palladia®) with piroxicam, vinblastine, and CCNU (lomustine) in dogs . Further investigations of multi‐drug chemotherapy protocols are warranted in veterinary oncology to strive for increased efficacy and improved outcomes in our companion animals with spontaneously arising tumours.…”

Section: Introductionmentioning

confidence: 99%

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Pellin

Wouda

Robinson

et al. 2016

Vet Comparative Oncology

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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 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 of DOX q 21 days given concurrently with toceranib 2.75 mg kg PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti-tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long-term AE profiles.

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“…Clinical toxicities associated with toceranib are primarily gastrointestinal side effects and neutropenia [27-31,38]. While lethargy was reported in 13% (3/23) of dogs during the 5 days of administration of LEC/chTNT-3, no gastrointestinal side effects were noted during this time.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 Dose-Escalation Study with LEC/Chtnt-3 and Toceranib Phosphate (Palladia) in Dogs with Spontaneous Malignancies

Jang

Chretin

Bruyette

et al. 2015

JCST

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Objectives LEC chemokine promotes TH1 responses and recruits immune cells to inflammatory sites. By linking LEC to an antibody targeting tumor necrosis, LEC/chTNT-3 can be used for the immunotherapeutic treatment of tumors. The primary objective of this study was to determine the safety profile of LEC/chTNT-3 and toceranib phosphate (Palladia®) combination therapy in dogs with spontaneous malignancies. Secondary purpose was to determine objective responses to treatment. Methods Twenty-three dogs with cancer were enrolled, covering nine different malignancies. In this dose escalation study, dogs received LEC/chTNT-3 for five days, and toceranib every 48 hours for the remainder of the study. Dogs received physical exams, chemistry panel, urinalysis, and complete blood counts on days 0, 10, 28 of the study, and every 6-8 weeks thereafter. Results Lethargy was noted in 13% dogs. There were no statistical differences in the prevalence of anorexia, diarrhea, thrombocytopenia, renal toxicity, or hepatic toxicity before or during the study. There were trends in increases in the prevalence of vomiting, lymphopenia, and neutropenia (all grade 2 or lower, p=0.07) over the initial 28 days of the study. By day 28, 10% of dogs had partial responses, 58% had stable disease, and 32% had progressive disease. Conclusions LEC/chTNT-3 and toceranib were well tolerated. This combination therapy showed some biological activity against a variety of cancers at a low dose and short duration of LEC/chTNT-3 administration.

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Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia^®) in tumour‐bearing dogs: a phase I dose‐finding study

Cited by 24 publications

References 47 publications

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Phase 1 Dose-Escalation Study with LEC/Chtnt-3 and Toceranib Phosphate (Palladia) in Dogs with Spontaneous Malignancies

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Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia®) in tumour‐bearing dogs: a phase I dose‐finding study

Cited by 24 publications

References 47 publications

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Phase 1 Dose-Escalation Study with LEC/Chtnt-3 and Toceranib Phosphate (Palladia) in Dogs with Spontaneous Malignancies

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Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia^®) in tumour‐bearing dogs: a phase I dose‐finding study