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Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial

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Abstract

Purpose

As part of a phase 1 dose-escalation trial, the pharmacodynamic activity of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus was assessed in multiple tissues by measuring levels of phosphorylated 4E binding protein-1 (p-4E-BP1) or S6, two downstream markers of mTOR activity.

Methods

32 patients (pts) were dosed intravenously with ridaforolimus once daily for 5 consecutive days (QD × 5) every 2 weeks. The pharmacodynamic activity of ridaforolimus was assessed in peripheral blood mononuclear cells (PBMCs; 32 pts), skin (28 pts), and tumor specimens (3 pts) collected before and after dosing by measuring levels of p-4E-BP1 by immunoblot analysis or pS6 by immunohistochemistry. Levels of these markers were assessed in up to 19, 5, and 2 pre- and post-dose time points in PBMC, skin, and tumor specimens, respectively.

Results

In preclinical models, ridaforolimus induced a dose-dependent inhibition of p-4E-BP1 in PBMCs that was associated with antitumor activity. Rapid and potent inhibition of mTOR was observed in PBMCs from all 32 pts dosed, with a median level of inhibition of 96% observed within 1 h after the first dose. Inhibition of mTOR (>90%) was sustained during the entire QD × 5 dosing period, and substantial inhibition was still observed after the 9-day holiday between dosing courses. Evidence of mTOR inhibition was also obtained in skin in pts from all dose cohorts, although it did not persist through the break between courses. After two to three doses of ridaforolimus, inhibition of mTOR was detected in the tumor from one of three pts analyzed.

Conclusions

Ridaforolimus was shown to inhibit its intended target, mTOR, in PBMCs, skin, and tumors. In PBMCs and skin, inhibition was observed at all dose levels tested, thus supporting but not driving the selection of a recommended phase 2 dose.

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References

  1. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945

    Article  PubMed  CAS  Google Scholar 

  2. Bjornsti M, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348

    Article  PubMed  CAS  Google Scholar 

  3. Rivera VM, Squillace RM, Miller D, Berk L, Wardwell SD, Ning Y, Pollock R, Narasimhan NI, Iuliucci JD, Wang F et al (2011) Ridaforolimus (AP23573, MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther 10:1059–1071

    Article  PubMed  CAS  Google Scholar 

  4. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD, Wyslouch-Cieszynska A, Aebersold R, Sonenberg N (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15:2852–2864

    Article  PubMed  CAS  Google Scholar 

  5. Dudkin L, Dilling MB, Cheshire PJ, Harwood FC, Hollingshead M, Arbuck SG, Travis R, Sausville EA, Houghton PJ (2001) Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7:1758–1764

    PubMed  CAS  Google Scholar 

  6. Mothe-Satney I, Brunn GJ, McMahon LP, Capaldo CT, Abraham RT, Lawrence JC Jr (2000) Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies. J Biol Chem 275:33836–33843

    Article  PubMed  CAS  Google Scholar 

  7. Peralba JM, DeGraffenried L, Friedrichs W, Fulcher L, Grunwald V, Weiss G, Hidalgo M (2003) Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887–2892

    PubMed  CAS  Google Scholar 

  8. Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, Tobler S, Heusser C, O’Reilly T, Stolz B et al (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252–261

    Article  PubMed  CAS  Google Scholar 

  9. O’Donnell A, Faivre S, Burris HA III, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595

    Article  PubMed  Google Scholar 

  10. Farag SS, Zhang S, Jansak BS, Wang X, Kraut E, Chan K, Dancey JE, Grever MR (2009) Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma. Leuk Res 33:1475–1480

    Article  PubMed  CAS  Google Scholar 

  11. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Ramon y Cajal S, Jones S, Vidal L et al (2008) Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26:1603–1610

    Article  PubMed  CAS  Google Scholar 

  12. Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T et al (2008) Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 26:361–367

    Article  PubMed  CAS  Google Scholar 

  13. Squillace RM, Miller D, Cookson M, Wardwell SD, Moran L, Clapham D, Wang F, Clackson T, Rivera VM (2011) Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther 10:1959–1968

    Google Scholar 

  14. Chen WW, Chan DC, Donald C, Lilly MB, Kraft AS (2005) Pim family kinases enhance tumor growth of prostate cancer cells. Mol Cancer Res 3:443–451

    Article  PubMed  CAS  Google Scholar 

  15. Pal SK, Figlin RA (2010) Treatment options in metastatic renal cell carcinoma: focus on mTOR inhibitors. Clin Med Insights Oncol 4:43–53

    PubMed  CAS  Google Scholar 

  16. Meric-Bernstam F, Gonzalez-Angulo AM (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27:2278–2287

    Article  PubMed  CAS  Google Scholar 

  17. Chapman JR, Valantine H, Albanell J, Arns WA, Campistol JM, Frigerio M, Lehmkuhl H, Marcen R, Morris R et al (2007) Proliferation signal inhibitors in transplantation: questions at the cutting edge of everolimus therapy. Transpl Proc 39:2937–2950

    Article  CAS  Google Scholar 

  18. O’Reilly T, McSheehy PM (2010) Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and further proposals. Transl Oncol 3:65–79

    PubMed  Google Scholar 

  19. Sleijfer S, Wiemer E (2008) Dose selection in phase I studies: why we should always go for the top. J Clin Oncol 26:1576–1578

    Article  PubMed  Google Scholar 

  20. Mahalingam D, Sankhala K, Mita A, Giles FJ, Mita MM (2009) Targeting the mTOR pathway using deforolimus in cancer therapy. Future Oncol 5:291–303

    Article  PubMed  CAS  Google Scholar 

  21. Hartford CM, Desai AA, Janisch L, Karrison T, Rivera VM, Berk L, Loewy JW, Kindler H, Stadler WM, Knowles HL et al (2009) A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies. Clin Cancer Res 15:1428–1434

    Article  PubMed  CAS  Google Scholar 

  22. Sessa C, Tosi D, Vigano L, Albanell J, Hess D, Maur M, Cresta S, Locatelli A, Angst R, Rojo F et al (2010) Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel. Ann Oncol 21:1315–1322

    Article  PubMed  CAS  Google Scholar 

  23. Perotti A, Locatelli A, Sessa C, Hess D, Vigano L, Capri G, Maur M, Cerny T, Cresta S, Rojo F et al (2010) Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine. J Clin Oncol 28:4554–4561

    Article  PubMed  CAS  Google Scholar 

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Author notes

  1. Camille L. Bedrosian

    Present address: Alexion Pharmaceuticals, Inc., Cheshire, CT, USA

Authors and Affiliations

  1. ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA, 02139, USA

    Lori Berk, Camille L. Bedrosian, Tim Clackson & Victor M. Rivera

  2. Cancer Therapy and Research Center, Institute for Drug Development, The University of Texas Health Science Center, San Antonio, TX, USA

    Monica M. Mita, Jeff Kreisberg & Anthony W. Tolcher

Authors
  1. Lori Berk
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  2. Monica M. Mita
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  3. Jeff Kreisberg
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  4. Camille L. Bedrosian
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  5. Anthony W. Tolcher
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  6. Tim Clackson
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  7. Victor M. Rivera
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Corresponding author

Correspondence to Victor M. Rivera.

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Berk, L., Mita, M.M., Kreisberg, J. et al. Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial. Cancer Chemother Pharmacol 69, 1369–1377 (2012). https://doi.org/10.1007/s00280-011-1813-7

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  • DOI: https://doi.org/10.1007/s00280-011-1813-7

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