Anna Mislang1, Richard Mollard2,3, Gonzalo Tapia Rico1,4, W Douglas Fairlie5,6,7, Erinna F Lee5,6,7, Tiffany J Harris5, Roger Aston8, Michael P Brown9,10,11,12. 1. Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, 5000, Australia. 2. PharmAust Ltd, Claremont, 6010, Australia. 3. Department of Veterinary and Agricultural Science, University of Melbourne, Parkville, 3052, Australia. 4. School of Medicine, University of Adelaide, Adelaide, 5000, Australia. 5. Olivia Newton-John Cancer Research Institute, Heidelberg, 3084, Australia. 6. School of Cancer Medicine, La Trobe University, Heidelberg, 3084, Australia. 7. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, VIC, 3086, Australia. 8. PharmAust Ltd, Claremont, 6010, Australia. rogeraston@aol.com. 9. Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, 5000, Australia. MichaelP.Brown@sa.gov.au. 10. Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, 5000, Australia. MichaelP.Brown@sa.gov.au. 11. School of Medicine, University of Adelaide, Adelaide, 5000, Australia. MichaelP.Brown@sa.gov.au. 12. Cancer Clinical Trials Unit, Department of Medical Oncology, 6E351, Royal Adelaide Hospital, Adelaide, 5000, Australia. MichaelP.Brown@sa.gov.au.
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.
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.
Entities:
Keywords:
Anthelmintic; Monepantel; Phase I study; Treatment-refractory cancer
Authors: Farnaz Bahrami; Mohammad H Pourgholami; Ahmed H Mekkawy; Lucien Rufener; David L Morris Journal: Am J Cancer Res Date: 2014-09-06 Impact factor: 6.166