Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 4, pp 727–733

A phase I trial of gemcitabine in combination with patupilone in patients with advanced solid tumors

  • William Schelman
  • Sherry Morgan-Meadows
  • Howard Bailey
  • Kyle Holen
  • James P. Thomas
  • Jens Eickhoff
  • Heidi Brandon
  • Kate Oliver
  • Dona Alberti
  • George Wilding
Clinical Trial Report

Abstract

Introduction

Chemotherapy regimens including gemcitabine in combination with microtubule inhibitors such as docetaxel and paclitaxel have wide clinical application. Patupilone is a novel tubulin-polymerizing agent with activity against paclitaxel-resistant cell lines. We conducted a phase I trial to assess the maximum tolerated dose, dose limiting toxicity (DLT) and antitumor activity of gemcitabine and patupilone.

Methods

Patients with refractory solid tumors enrolled in cohorts of three. Cohorts received fixed doses of gemcitabine (1,000 or 750 mg/m2) along with escalating doses of patupilone (1.5–3 mg/m2) on days 1 and 8 of a 21-day cycle.

Results

Twenty-seven patients received a total of 99 courses of treatment on study. Hematologic toxicity in the first cohort required a modification of the protocol to decrease the gemcitabine dose. Subsequent patients received gemcitabine 750 mg/m2 and escalating doses of patupilone from 1.5 to 3 mg/m2. DLTs were grade 3 asthenia and grade 3 dehydration. There was also one treatment-related death due to neutropenic infection. Other clinically significant toxicities were persistent asthenia and persistent nausea. Four patients, one each with pancreatic cancer, esophageal carcinoma, cholangiocarcinoma and gallbladder carcinoma, experienced a partial response.

Conclusions

The dose-limiting toxicities of gemcitabine and patupilone were asthenia and dehydration. Dose reductions also occurred due to persistent fatigue that was not dose-limiting. However, patients with advanced malignancies were able to tolerate gemcitabine and patupilone at doses that resulted in clinical benefit. The recommended phase II dose for this schedule is gemcitabine 750 mg/m2 and patupilone 1.5 mg/m2 on days 1 and 8 of a 21-day cycle.

Keywords

Gemcitabine Patupilone Chemotherapy Phase I 

References

  1. 1.
    Jordan MA, Thrower D, Wilson L (1991) Mechanism of inhibition of cell proliferation by vinca alkaloids. Cancer Res 51:2212–2222PubMedGoogle Scholar
  2. 2.
    Jordan MA, Toso RJ, Thrower D et al (1993) Mechanism of mitotic block and inhibition of cell proliferation by Taxol at low concentrations. Proc Natl Acad Sci USA 90:9552–9556PubMedCrossRefGoogle Scholar
  3. 3.
    Ling V (1992) Charles F. Kettering prize: P-glycoprotein and resistance to anticancer drugs. Cancer 69:2603–2609PubMedCrossRefGoogle Scholar
  4. 4.
    Kowalski RJ, Giannakakou P, Hamel E (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272:2534–2541PubMedCrossRefGoogle Scholar
  5. 5.
    Bollag DM, McQueney PA, Zhu J et al (1995) Epothilones, a new class on microtubule-stabilizing agents with a Taxol-like mechanism of action. Cancer Res 55:2325–2333PubMedGoogle Scholar
  6. 6.
    Kowalski RJ, Giannakakou P, Hamel E (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purifies tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272:2534–2541PubMedCrossRefGoogle Scholar
  7. 7.
    Wenger F, Duboc L, Tinetto W, O’Reilly T. CGP 47906 (epothilone B) is active in models of ovarian and glioma tumors. Release Ready Report PKF-98-01821. July 31, 1998Google Scholar
  8. 8.
    Wartmann M, Woods-Cook K, Mett H. In vitro cytotoxicity profile of the antimicrotubule agent EPO906 (CCP 47906, epothilone B) in comparison with paclitaxel. Release Ready Report PKF-98-03317. Nov. 24, 1998Google Scholar
  9. 9.
    Calvert PM, O’Neill V, Twelves C, Azzabi A, Hughes A, Bale C, Robinson A, Machan M, Dimitrijevic S, Moss D, Rothermel J, Cohen P, Chen T, Man A, Calvert AH (2001) A phase I clinical and pharmacokinetic study of EPO906 (epothilone B), given every three weeks, in patients with advanced solid tumors. Proc Am Soc Clin Oncol 20:108, (abstr 429)Google Scholar
  10. 10.
    Rubin EH, Rothermel J, Tesfaye Chen T, Hubert M, Ho Y-Y, Hsu C-H, Oza AM (2005) Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 23:9120–9129PubMedCrossRefGoogle Scholar
  11. 11.
    Hussain A, Dipaola RS, Baron AD, Higano CS, Tchekmediyan NS, Miller JA, Rothermel JD (2004) A phase IIa trial of weekly EPO906 in patients with hormone-refractory prostate cancer. Proc Am Soc Clin Oncol 22:397, (abstr 4563)Google Scholar
  12. 12.
    Goodin S, Kane MP, Rubine ER (2004) Epothilones: mechanism of action and biologic activity. J Clin Oncol 22:2015–2025PubMedCrossRefGoogle Scholar
  13. 13.
    Thompson JA, Swerdloff J, Escudier B, Dutcher JP, Bukowski RM, Vaishampayan U, Hussein A, Negrier S, Rothermel J (2004) Phase II trial evaluating the safety and efficacy of EPO906 in patients with advanced renal cancer. Proc Am Soc Clin Oncol 22:405, (abstr 1628)Google Scholar
  14. 14.
    Fleming DR, Glisson SD, Bhupalam L et al (2000) Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies. Am J Clin Oncol 23(4):349–352PubMedCrossRefGoogle Scholar
  15. 15.
    Thomas AL, Cox G, Sharma RA et al (2000) Gemcitabine and paclitaxel associated pneumomitis in non-small cell lung cancer: report of a phase I/II dose-escalating study. Eur J Cancer 36:2329–2334PubMedCrossRefGoogle Scholar
  16. 16.
    Isla D, Rosell R, Sánchez JJ, Carrato A et al (2001) Phase II trial of paclitaxel plus gemcitabine in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 19(4):1071–1077PubMedGoogle Scholar
  17. 17.
    Murad AM, Guimarães RC, Aragão BC et al (2001) Phase II trial of the use of paclitaxel and gemcitabine as salvage treatment in metastatic breast cancer. Am J Clin Oncol 24(3):264–268PubMedCrossRefGoogle Scholar
  18. 18.
    Ryan DP, Lynch TJ, Grossbard ML et al (2002) A phase I study of gemcitabine and docetaxel in patients with metastatic solid tumors. Cancer 88:180–185CrossRefGoogle Scholar
  19. 19.
    Hejna M, Kornek GV, Raderer M et al (2000) Treatment of patients with advanced nonsmall cell lung carcinoma using docetaxel and gemcitabine plus granulocyte-colony stimulating factor. Cancer 89:516–522PubMedCrossRefGoogle Scholar
  20. 20.
    Bhargava P, Marshall JL, Fried K et al (2001) Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer. Cancer Chemother Pharmacol 48:95–103PubMedCrossRefGoogle Scholar
  21. 21.
    Delfino C, Caccia G, Riva Gonzales L, Mickiewicz E, Rodger J, Babliani L, Flores Morales D, Zori Comba A, Brosio C (2003) Gemcitabine/paclitaxel as first-line treatment of advanced breast cancer. Oncology 17:22–25PubMedGoogle Scholar
  22. 22.
    Kornek GV, Haider K, Kwansy W, Raderer M, Schull B, Payrits T, Depisch D, Kovats E, Lang F, Scheithauer W (2002) Treatment of advanced breast cancer with docetaxel and gemcitabine with and without human granulocyte colony-stimulating factor. Clin Cancer Res 8:1051–1056PubMedGoogle Scholar
  23. 23.
    Chen YM, Perng RP, Lin WC, Wu HW, Tsai CM, Whan-Peng J (2002) Phase II study of docetaxel and gemcitabine combination chemotherapy in non-small cell lung cancer patients failing previous chemotherapy. Am J Clin Oncol 25:509–512PubMedCrossRefGoogle Scholar
  24. 24.
    Kosmoas C, Tsavairs N, Vadiaka M, Stavroyianni N, Koutras A, Malamos N, Onyenadum A, Rokana S, Polyzos A, Kalofonos HP (2001) Gemcitabine and docetaxel as second-line chemotherapy for patients with nonsmall cell lung carcinoma who fail prior paclitaxel plus platinum-based regimens. Cancer 92:2902–2910CrossRefGoogle Scholar
  25. 25.
    Hainsworht JD, Burris HA 3rd, Billings FT 3rd, Bradof JE, Baker M, Greco FA (2001) Weekly docetaxel with either gemcitabine or vinorelbine as second-line treatment in patients with advanced nonsmall cell lung carcinoma: phase II trials of the Minnie pearl cancer research network. Cancer 92:2391–2398CrossRefGoogle Scholar
  26. 26.
    Giaccone G, Smit EF, van Meerbeeck JP, Splinter T, Golding RP, Pinedo HM, Laan D van Tinteren H, Postmus PE (2000) A phase I-II study of gemcitabine and paclitaxel in advanced non-small-cell lung cancer patients. Ann Oncol 11:109–112PubMedCrossRefGoogle Scholar
  27. 27.
    Pouessel D, Culine S, BEcht C, Romieu G, Gabbro M, Ychou M, Cupissol D, Pinguet F (2004) Gemcitabine and docetaxel after failure of cisplatin-based chemotherapy in patients with carcinoma of unknown primary site. Anticancer Res 23:2801–2804Google Scholar
  28. 28.
    Dreicer R, Manola J, Schneider DJ, Schwerkoske JF, George CS, Roth BJ, Wilding G (2003) Phase II trial of gemcitabine and docetaxel in patients with advanced carcinoma of the urothelium: a trial of the eastern cooperative oncology group. Cancer 97:2743–2747PubMedCrossRefGoogle Scholar
  29. 29.
    Li J, Juliar B, Yiannoutsos C, Ansari R, Fox E, Fisch MJ, Einhorn LH, Sweeney CJ (2005) Weekly paclitaxel and gemcitabine in advanced transitional-cell carcinoma of the urothelium: a phase II Hoosier oncology group study. J Clin Oncol 23:1185–1191PubMedCrossRefGoogle Scholar
  30. 30.
    Gitlitz BJ, Baker C, Chapman Y, Allen HJ, Bosserman LD, PAtel R, Sanchez JD, Shapiro RM, Figlin RA (2003) A phase II study of gemcitabine and docetaxel therapy in patients with advanced urothelial carcinoma. Cancer 98:1863–1869PubMedCrossRefGoogle Scholar
  31. 31.
    Kuhn R, Hribaschek A, Eichelmann K, Rudolph S, Fahlke J, Ridwelski K (2002) Outpatient therapy with gemcitabine and docetaxel for gallbladder, biliary and cholangiocarcinomas. Invest New Drugs 20:351–356PubMedCrossRefGoogle Scholar
  32. 32.
    Shepard RC, Levy DE, Berlin JD, Stuart K, Harris JE, Aviles V, Thomas JP, Benson AB 3rd (2004) Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298). A trial of the eastern cooperative oncology group. Oncology 66(4):303–309PubMedCrossRefGoogle Scholar
  33. 33.
    Schneider BP, Ganjoo KN, Seitz DE, Picus J, Fata F, Stoner C, Calley C, Loehrer PJ (2003) Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: a Hoosier oncology group study. Oncology 65(3):218–223PubMedCrossRefGoogle Scholar
  34. 34.
    Tsuchida Y, Therasse P (2001) Response evaluation criteria in solid tumors (RECIST): new guidelines. Med Pediatr Oncol 37:1–3PubMedCrossRefGoogle Scholar
  35. 35.
    Poplin E, Moore M, O’Dwyer P, Clarke S, Hill M, Sessa C, Rothermel J, Jull R, Miller J, Rosen L (2004) Safety and efficacy of EPO906 in patients with advanced colorectal cancer: a review of 2 phase II trials. Proc Am Soc Clin Oncol 22:283, (abstr 1135)Google Scholar
  36. 36.
    Smit WM, Sufliarsky J, Spanik S, Wagnerová M, Kaye S, Oza AM, Gore M, Williams K, Jorhi A, Ten Bokkel Huinink WW (2005) Phase I/II dose-escalation trial of patupilone every 3 weeks in patients with relapsed/refractory ovarian cancer. Proc Am Soc Clin Oncol 23:468, (abstr 5056)Google Scholar
  37. 37.
    Melichar B, Tabernor J, Casodo E, Bridgewater J, Hamm J, Sklenar I, Holland J, Cheung W, Zaknoen S, Johri A (2005) Phase I dose optimization trial of patupilone in previously treated patients with advanced colon cancer. Proc Am Soc Clin Oncol 23:292, (abstr 3688)Google Scholar
  38. 38.
    Rinehart JJ, Rothermel JD, Anderson J, Lorusso P (2004) Phase I dose-escalation trial investigating the safety and tolerability of EPO906 plus gemcitabine in patients with advanced cancer. Proc Am Soc Clin Oncol 22:14S, (abstr 3100)Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • William Schelman
    • 1
  • Sherry Morgan-Meadows
    • 1
    • 2
  • Howard Bailey
    • 1
  • Kyle Holen
    • 1
  • James P. Thomas
    • 1
    • 3
  • Jens Eickhoff
    • 1
  • Heidi Brandon
    • 1
  • Kate Oliver
    • 1
  • Dona Alberti
    • 1
  • George Wilding
    • 1
  1. 1.University of Wisconsin Paul P. Carbone Comprehensive Cancer CenterMadisonUSA
  2. 2.Southern Cancer CenterMobileUSA
  3. 3.The Ohio State University Comprehensive Cancer CenterColumbusUSA

Personalised recommendations