Advertisement

Investigational New Drugs

, Volume 31, Issue 5, pp 1339–1344 | Cite as

Patupilone in patients with pretreated metastatic/locally recurrent colorectal cancer: results of the Phase II CINATRA trial

  • S. Y. Moorcraft
  • I. ChauEmail author
  • C. Peckitt
  • D. Cunningham
  • S. Rao
  • K. L. Yim
  • A. Walther
  • C. G. C. A. Jackson
  • G. Stamp
  • J. Webb
  • G. Smith
  • A. Gillbanks
  • C. Swanton
PHASE II STUDIES

Summary

Background Phase I trials of the microtubule stabilising agent patupilone showed encouraging tumour control and response rates in patients with metastatic colorectal cancer. Methods Patients with metastatic or locally recurrent colorectal cancer who had progressed following treatment with oxaliplatin, irinotecan and fluoropyrimidines were treated with patupilone (8 mg/m2 IV every 3 weeks) in combination with dexamethasone or prednisolone. Results The trial was closed early after 29 patients had been enrolled due to concerns about toxicity. 20 patients (71.4 %) experienced at least one grade 3–5 toxicity, most commonly diarrhoea (14 patients), dehydration (7 patients) and lethargy (6 patients). The 12 week progression-free survival rate was 16.7 % (95 % CI 6.1 %–36.5 %) in the 24 patients with a 12 week scan available or who had died prior to the 12 week scan. No complete or partial responses were seen by 12 weeks. The median progression-free survival was 2.6 months (95 % CI 2.3–2.9) and median overall survival was 6.1 months (95 % CI 3.7–8.4). Conclusion Patupilone given at a dose of 8 mg/m2 IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre-treated colorectal cancer.

Keywords

Patupilone Colorectal cancer Toxicity Diarrhoea 

Notes

Acknowledgements

We acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre and Novartis who provided an educational grant and patupilone.

Ethical standards

The study was approved by a Research Ethics Committee and all patients provided written informed consent.

Conflicts of interest

IC has received research funding from Novartis, Merck-Serono and Roche, and has advisory roles (compensated) with Roche, Sanofi-Aventis, Novartis and Eli Lilly. DC has received research funding from Amgen, Roche, Sanofi-Aventis, Merck-Serono, Novartis, and Celgene, and has had advisory roles (uncompensated) with Roche and Amgen. SR has received research funding from GlaxoSmithKline and has advisory roles (uncompensated) with Roche, Sanofi-Aventis, Merck-Serono and Celgene. CS sat on a global advisory board for Novartis 3 years ago and receives research funding from Novartis. SYM, CP, KLY, AW, CJ, GS, JW, GSm and AG have no conflicts of interest to declare.

References

  1. 1.
    Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N (2010) Colorectal cancer. Lancet 375(9719):1030–1047. doi: https://doi.org/10.1016/S0140-6736(10)60353-4 CrossRefGoogle Scholar
  2. 2.
    Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Annal Oncol Off J Eur Soc Med Oncol / ESMO 18(3):581–592. doi: https://doi.org/10.1093/annonc/mdl498 CrossRefGoogle Scholar
  3. 3.
    Walther A, Johnstone E, Swanton C, Midgley R, Tomlinson I, Kerr D (2009) Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer 9(7):489–499. doi: https://doi.org/10.1038/nrc2645 CrossRefGoogle Scholar
  4. 4.
    Swanton C, Tomlinson I, Downward J (2006) Chromosomal instability, colorectal cancer and taxane resistance. Cell cycle 5(8):818–823CrossRefGoogle Scholar
  5. 5.
    Bystricky B, Chau I (2011) Patupilone in cancer treatment. Expert Opin Investigational Drugs 20(1):107–117. doi: https://doi.org/10.1517/13543784.2011.542148 CrossRefGoogle Scholar
  6. 6.
    Anand S, Penrhyn-Lowe S, Venkitaraman AR (2003) AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer cell 3(1):51–62CrossRefGoogle Scholar
  7. 7.
    Melichar B, Casado E, Bridgewater J, Bennouna J, Campone M, Vitek P, Delord JP, Cerman J Jr, Salazar R, Dvorak J, Sguotti C, Urban P, Viraswami-Appanna K, Tan E, Tabernero J (2011) Clinical activity of patupilone in patients with pretreated advanced/metastatic colon cancer: results of a phase I dose escalation trial. Br J Cancer 105(11):1646–1653. doi: https://doi.org/10.1038/bjc.2011.438 CrossRefGoogle Scholar
  8. 8.
    Iqbal S, El-Khoueiry AB, Yang D, Cole S, Boswell W, Shriki J, Ning Y, Agafitei RD, Menendez X, Lenz H (2010) A phase I study of celecoxib (C) and patupilone (EPO906) in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol Off J Am S Clin Oncol 28 (suppl; abstr 2533)CrossRefGoogle Scholar
  9. 9.
    McSheehy P, Becquet M, Boisclair J, Bizot MN (2008) Prednisolone abrogates patupilone (EPO906)-induced diarrhoea in rats without impacting on patupilone PK or efficacy. Proc 20th EORTC-NCI-AACR Symp Mol Targets Cancer Ther EJC Suppl 6:451Google Scholar
  10. 10.
    Sridhar SS, Hotte SJ, Kollmannsberger CK, Mukherjee SD, Capier K, Barclay J, Adams L, Weber D, Chi KN (2010) Preventing patupilone-induced diarrhea with high-dose corticosteroids. J Clin Oncol Off J Am S Clin Oncol 28 (suppl; abstr e13069)Google Scholar
  11. 11.
    Kornblau S, Benson AB, Catalano R, Champlin RE, Engelking C, Field M, Ippoliti C, Lazarus HM, Mitchell E, Rubin J, Stiff PJ, Vokes E, Wadler S (2000) Management of cancer treatment-related diarrhea. Issues and therapeutic strategies. J Pain Symptom Manag 19(2):118–129CrossRefGoogle Scholar
  12. 12.
    Wadler S, Benson AB 3rd, Engelking C, Catalano R, Field M, Kornblau SM, Mitchell E, Rubin J, Trotta P, Vokes E (1998) Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol Off J Am S Clin Oncol 16(9):3169–3178CrossRefGoogle Scholar
  13. 13.
    Poplin E, Moore M, O'Dwyer P, Clarke S, Hill M, Sessa C, Rothermel J, Mull R, Miller J, L; R (2003) Safety and efficacy of EPO906 in patients with advanced colorectal cancer: A review of 2 phase II trials Proc Am Soc Clin Oncol 22 (abstr 1135)Google Scholar
  14. 14.
    Colombo N, Kutarska E, Dimopoulos M, Bae DS, Rzepka-Gorska I, Bidzinski M, Scambia G, Engelholm SA, Joly F, Weber D, El-Hashimy M, Li J, Souami F, Wing P, Engelholm S, Bamias A, Schwartz P (2012) Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. J Clin Oncol Off J Am S Clin Oncol 30(31):3841–3847. doi: https://doi.org/10.1200/JCO.2011.38.8082 CrossRefGoogle Scholar
  15. 15.
    Hussain A, DiPaola RS, Baron AD, Higano CS, Tchekmedyian NS, Johri AR (2009) Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer. Annal Oncol Off J Eur Soc Med Oncol / ESMO 20(3):492–497. doi: https://doi.org/10.1093/annonc/mdn665 CrossRefGoogle Scholar
  16. 16.
    Reid TR, Takimoto CH, Verschraegen CF, Sarantopoulos J, Cheung W, Allen-Freda E, Li J, Xu Y, Ko J, Johri A (2008) Evaluation of safety, tolerability and pharmacokinetics (PK) of patupilone in patients (pts) with advanced solid tumors and varying degrees of hepatic function: An open-label phase I study. J Clin Oncol Off J Am S Clin Oncol 26: (May 20 suppl; abstr 2557)Google Scholar
  17. 17.
    Chi KN, Beardsley E, Eigl BJ, Venner P, Hotte SJ, Winquist E, Ko YJ, Sridhar SS, Weber D, Saad F (2012) A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian Urologic Oncology Group study P07a. Annal Oncol Off J Eur Soc Med Oncol / ESMO 23(1):53–58. doi: https://doi.org/10.1093/annonc/mdr336 CrossRefGoogle Scholar
  18. 18.
    Abrey LE, Wen P, Govindan R, Reimers H, Rigas JR, Robins HI, Allen-Freda E, Gao B, Ko J, Johri A (2008) Patupilone for the treatment of recurrent/progressive brain metastases in patients (pts) with non-small cell lung cancer (NSCLC): An open-label phase II study. J Clin Oncol Off J Am S Clin Oncol 26: (May 20 suppl; abstr 2033)Google Scholar
  19. 19.
    De Souza PL, Mellado B, Pfister C, Rosenthal M, Castellano DE, Weber D, Ferrara S, Shaik N, Tan E, S.G; P (2010) Randomized phase II trial of patupilone plus prednisone versus docetaxel plus prednisone in patients with chemotherapy-naïve, metastatic, castrate-resistant prostate cancer (CRPC). J Clin Oncol Off J Am S Clin Oncol 28 (suppl; abstr 4553)Google Scholar
  20. 20.
    Oehler C, Frei K, Rushing EJ, McSheehy PM, Weber D, Allegrini PR, Weniger D, Lutolf UM, Knuth A, Yonekawa Y, Barath K, Broggini-Tenzer A, Pruschy M, Hofer S (2012) Patupilone (epothilone B) for recurrent glioblastoma: clinical outcome and translational analysis of a single-institution phase I/II trial. Oncology 83(1):1–9. doi: https://doi.org/10.1159/000339152 CrossRefGoogle Scholar
  21. 21.
    Conlin AK, D'Andrea G, Hudis CA, Robson ME, Drullinsky P, Theodoulou M, Lis E, Kang TY, Peereboom DM, Seidman AD (2008) Phase II trial of patupilone in patients (pts) with breast cancer brain metastases (BCBM) progressing or recurring after whole brain radiation therapy (WBXRT) Journal of Clinical Oncology 26 (May 20 Suppl;1086)Google Scholar
  22. 22.
    Rubin EH, Rothermel J, Tesfaye F, Chen T, Hubert M, Ho YY, Hsu CH, Oza AM (2005) Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol Off J Am S Clin Oncol 23(36):9120–9129. doi: https://doi.org/10.1200/JCO.2005.03.0981 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • S. Y. Moorcraft
    • 1
  • I. Chau
    • 1
    Email author
  • C. Peckitt
    • 1
  • D. Cunningham
    • 1
  • S. Rao
    • 1
  • K. L. Yim
    • 2
  • A. Walther
    • 3
  • C. G. C. A. Jackson
    • 4
  • G. Stamp
    • 1
  • J. Webb
    • 1
  • G. Smith
    • 1
  • A. Gillbanks
    • 1
  • C. Swanton
    • 5
  1. 1.The Royal MarsdenSuttonUK
  2. 2.Velindre Cancer CentreCardiffUK
  3. 3.University Hospitals BristolBristolUK
  4. 4.Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand
  5. 5.Translational Cancer Therapeutics LaboratoryCR-UK London Research InstituteLondonUK

Personalised recommendations