Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/24943
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dc.contributor.authorMislang, Anna-
dc.contributor.authorMollard, Richard-
dc.contributor.authorTapia Rico, Gonzalo-
dc.contributor.authorFairlie, Walter Douglas-
dc.contributor.authorLee, Erinna F-
dc.contributor.authorHarris, Tiffany J-
dc.contributor.authorAston, Roger-
dc.contributor.authorBrown, Michael P-
dc.date2020-09-22-
dc.date.accessioned2020-10-02T03:26:56Z-
dc.date.available2020-10-02T03:26:56Z-
dc.date.issued2020-11-
dc.identifier.citationCancer Chemotherapy and Pharmacology 2020; 86(5): 589-594en
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/24943-
dc.description.abstractMonepantel is an approved veterinary anthelmintic with a strong safety profile. Preclinical evidence suggests novel mTOR pathway-associated anticancer activity. An open-label Phase I trial assessed tolerability, pharmacokinetics, pharmacodynamics and PET-CT imaging following oral Zolvix® monepantel administration to adults with treatment refractory, progressing and unresectable solid tumors. Subjects were scheduled to daily home-based monepantel administration for 28 days in a 3 + 3 dose escalation study (5.0, 25.0 and 62.5 mg/kg bw). Of 41 reported drug-related AEs, 68% were Grade 1 and 24% were Grade 2; 35 AEs related to gastrointestinal effects including very poor palatability. DLT and MTD could not be determined due to early termination. Myelosuppression was not observed at the lowest level tested. Three of four Cohort 1 subjects had reduced mTOR pathway marker p-RPS6KB1 levels in PBMCs and achieved RECISTv1.1 SD by CT; one had progressive bony metastases by FDG-PET. One subject recorded PD on day 28, correlating with no detectable plasma monepantel from day 7. Monepantel sulfone dominated monepantel in pharmacokinetics. Both Cohort 2 subjects withdrew early due to AEs and the trial was terminated. Short-term 5 mg/kg bw monepantel administration provides a combined steady-state trough plasma monepantel and monepantel sulfone concentration of 0.5 μM. Gastrointestinal AEs including very poor palatability are concerning and suggested to be resolved by future drug product reformulation. RECISTv1.1, p-RPS6KB1 and plasma tumor marker outcomes provide preliminary evidence of anticancer activity.en
dc.language.isoeng-
dc.subjectAnthelminticen
dc.subjectMonepantelen
dc.subjectPhase I studyen
dc.subjectTreatment-refractory canceren
dc.titleA preliminary assessment of oral monepantel's tolerability and pharmacokinetics in individuals with treatment-refractory solid tumors.en
dc.typeJournal Articleen
dc.identifier.journaltitleCancer Chemotherapy and Pharmacologyen
dc.identifier.affiliationCancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, 5000, Australiaen
dc.identifier.affiliationSchool of Cancer Medicine, La Trobe University, Heidelberg, 3084, Australiaen
dc.identifier.affiliationOlivia Newton-John Cancer Research Instituteen
dc.identifier.affiliationDepartment of Veterinary and Agricultural Science, University of Melbourne, Parkville, 3052, Australiaen
dc.identifier.affiliationSchool of Medicine, University of Adelaide, Adelaide, 5000, Australiaen
dc.identifier.affiliationCentre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, 5000, Australiaen
dc.identifier.affiliationDepartment of Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, VIC, 3086, Australiaen
dc.identifier.affiliationPharmAust Ltd, Claremont, 6010, Australiaen
dc.identifier.affiliationCancer Clinical Trials Unit, Department of Medical Oncology, 6E351, Royal Adelaide Hospital, Adelaide, 5000, Australiaen
dc.identifier.doi10.1007/s00280-020-04146-5en
dc.type.contentTexten
dc.identifier.orcid0000-0002-5796-1932en
dc.identifier.pubmedid32960289-
local.name.researcherFairlie, Walter Douglas
item.languageiso639-1en-
item.cerifentitytypePublications-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.grantfulltextnone-
item.openairetypeJournal Article-
item.fulltextNo Fulltext-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
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