Cancer Chemother Pharmacol

. 2020 Sep 22.

doi: 10.1007/s00280-020-04146-5. Online ahead of print.

A preliminary assessment of oral monepantel's tolerability and pharmacokinetics in individuals with treatment-refractory solid tumors

Anna Mislang ¹, Richard Mollard ^{2 3}, Gonzalo Tapia Rico ^{1 4}, W Douglas Fairlie ^{5 6 7}, Erinna F Lee ^{5 6 7}, Tiffany J Harris ⁵, Roger Aston ⁸, Michael P Brown ^{9 10 11 12}

Affiliations collapse

Affiliations

• ¹Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, 5000, Australia.
• ²PharmAust Ltd, Claremont, 6010, Australia.
• ³Department of Veterinary and Agricultural Science, University of Melbourne, Parkville, 3052, Australia.
• ⁴School of Medicine, University of Adelaide, Adelaide, 5000, Australia.
• ⁵Olivia Newton-John Cancer Research Institute, Heidelberg, 3084, Australia.
• ⁶School of Cancer Medicine, La Trobe University, Heidelberg, 3084, Australia.
• ⁷Department of Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, VIC, 3086, Australia.
• ⁸PharmAust Ltd, Claremont, 6010, Australia. [email protected].
• ⁹Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, 5000, Australia. [email protected].
• ¹⁰Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, 5000, Australia. [email protected].
• ¹¹School of Medicine, University of Adelaide, Adelaide, 5000, Australia. [email protected].
• ¹²Cancer Clinical Trials Unit, Department of Medical Oncology, 6E351, Royal Adelaide Hospital, Adelaide, 5000, Australia. [email protected].

• PMID: 32960289

DOI: 10.1007/s00280-020-04146-5

Abstract

Purpose: Monepantel 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Anthelmintic; Monepantel; Phase I study; Treatment-refractory cancer.

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