Investigational New Drugs

, Volume 29, Issue 5, pp 1057–1065 | Cite as

Thymidylate synthase (TYMS) enhancer region genotype-directed phase II trial of oral capecitabine for 2nd line treatment of advanced pancreatic cancer

  • Colin D. Weekes
  • Sujatha Nallapareddy
  • Michelle A. Rudek
  • Alexis Norris-Kirby
  • Daniel Laheru
  • Antonio Jimeno
  • Ross C. Donehower
  • Kathleen M. Murphy
  • Manuel Hidalgo
  • Sharyn D. Baker
  • Wells A. Messersmith
PHASE II STUDIES

Summary

Purpose The primary aim of this study was to characterize the 6-month overall survival and toxicity associated with second-line capecitabine treatment of advanced pancreatic cancer patients harboring the TYMS *2/*2 allele. The secondary aim was to analyze the response rate and pharmacokinetics of capecitabine-based therapy in this patient population. Lastly, TYMS, ATM and RecQ1 single nucleotide polymorphism were analyzed relative to overall survival in patients screened for study participation. Methods Eighty patients with stage IV pancreatic cancer were screened for the *2/*2 TYMS allele. Patients with the *2/*2 TYMS polymorphism were treated with capecitabine, 1,000 mg/m2 twice daily for 14 consecutive days of a 21 day cycle. Screened patients not possessing TYMS *2/*2 were monitored for survival. Pharmacokinetic analysis was done during Cycle 1 of the therapy. Results Sixteen of the 80 screened patients tested positive for *2/*2 TYMS variant. Four out of the 16 eligible patients were treated on study. The study was terminated early due to poor accrual and increased toxicity. Three patients experienced grade 3 non-hematologic toxicities of palmer-plantar erythrodysesthesia, diarrhea, nausea and vomiting. Grade 2 toxicities were similar and occurred in all patients. Only one patient was evaluable for response after completion of three cycles of therapy. The presence of the *2/*2 TYMS genotype in all of the screened patients trended toward a decreased overall survival. Conclusion To our knowledge, this study represents the first genotype-directed clinical trial for patients with pancreatic adenocarcinoma. Although the study was closed early, it appears capecitabine therapy in pancreatic cancer patients harboring the TYMS *2/*2 variant may be associated with increased non-hematologic toxicity. This study also demonstrates the challenges performing a genotype-directed study in the second-line setting for patients with advanced pancreatic cancer.

Keywords

Pancreatic cancer Thymidine synthase enhancer region (TYMS) Capecitabine Gemcitabine RecQ1 ATM 

References

  1. 1.
    American Cancer Society (2009) Cancer facts and figuresGoogle Scholar
  2. 2.
    Yeo TP, Hruban RH, Leach SD, Wilentz RE, Sohn TA, Kern SE et al (2002) Pancreatic cancer. Curr Probl Cancer 26(4):176–275PubMedCrossRefGoogle Scholar
  3. 3.
    Abrams RA, Grochow LB, Chakravarthy A, Sohn TA, Zahurak ML, Haulk TL et al (1999) Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels. Int J Radiat Oncol Biol Phys 44(5):1039–1046PubMedCrossRefGoogle Scholar
  4. 4.
    Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA et al (2000) Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indications. J Gastrointest Surg 4(6):567–579PubMedCrossRefGoogle Scholar
  5. 5.
    Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413PubMedGoogle Scholar
  6. 6.
    Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schuller J et al (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the swiss group for clinical cancer research and the central European cooperative oncology group. J Clin Oncol 25(16):2212–2217PubMedCrossRefGoogle Scholar
  7. 7.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25(15):1960–1966PubMedCrossRefGoogle Scholar
  8. 8.
    Volker H, Quietzcsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A et al (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24(24):3946–3952CrossRefGoogle Scholar
  9. 9.
    Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T et al (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23(15):3509–3516PubMedCrossRefGoogle Scholar
  10. 10.
    Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M et al (2005) A phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23(31):8033–8040PubMedCrossRefGoogle Scholar
  11. 11.
    Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem J-L et al (2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 27(13):2231–2237PubMedCrossRefGoogle Scholar
  12. 12.
    Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JHM, Grochow LB et al (2002) Role of body surface area in dosing of investigational anticancer agents in adults, 1991–2001. JNCI Cancer Spectrum 94:1883–1888Google Scholar
  13. 13.
    Johnston PG, Drake JC, Trepel J, Allegra C (1992) Immunological quantitation of Thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and –resistant human cancer cell lines. Cancer Res 52:4306–4312PubMedGoogle Scholar
  14. 14.
    Johnston PG, Lenz HJ, Leichman CG, Danenberg K, Allegra CJ, Danenberg PV et al (1995) Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 55:1407–1412PubMedGoogle Scholar
  15. 15.
    Leichman CG, Lenz HJ, Leichman L, Danenberg K, Baranda J, Groshen S et al (1997) Quantitation of intratumoral Thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol 15:3223–3229PubMedGoogle Scholar
  16. 16.
    Horie N, Aiba H, Katsuhiko O, Hojo H, Takeishi K (1995) Functional analysis of DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 20:191–197PubMedCrossRefGoogle Scholar
  17. 17.
    Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz H-J et al (2003) A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the Thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 63:2898–2904PubMedGoogle Scholar
  18. 18.
    Villafranca E, Okruzhnov Y, Dominguez MA, Garcia-Foncillas J, Azinovic I, Martinez E et al (2001) Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 19:1779–1786PubMedGoogle Scholar
  19. 19.
    Park DJ, Stoehlmacher J, Zhang W, Tsao-Wei D, Groshen S, Lenz H-J (2002) Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer. Int J Colorectal Dis 17:46–49PubMedCrossRefGoogle Scholar
  20. 20.
    Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L et al (2000) Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45(4):291–297PubMedCrossRefGoogle Scholar
  21. 21.
    Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV et al (2002) Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 20(1):160–164PubMedCrossRefGoogle Scholar
  22. 22.
    Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W et al (2009) Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27(33):5513–5518PubMedCrossRefGoogle Scholar
  23. 23.
    Fukunaga AK, Marsh S, Murry DJ, Hurley TD, McLeod HL (2004) Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway. Pharmacogenomics J 4(5):307–314PubMedCrossRefGoogle Scholar
  24. 24.
    Mini E, Nobili S, Caciagli B, Landini I, Mazzei T (2006) Cellular pharmacology of gemcitabine. Ann Oncol 17(Suppl 5):7–12CrossRefGoogle Scholar
  25. 25.
    Li D, Frazier M, Evans DB, Hess KR, Crane CH, Jiao L et al (2006) Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with reduced survival of pancreatic cancer. J Clin Oncol 24(11):1720–1728PubMedCrossRefGoogle Scholar
  26. 26.
    Okazaki T, Jiao L, Chang P, Evans DB, Abbruzzese JL, Li D (2008) Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer. Clin Cancer Res 14(7):2042–2048PubMedCrossRefGoogle Scholar
  27. 27.
    Xu Y, Grem JL (2003) Liquid chromatography-mass spectrometry method for the analysis of the anti-cancer agent capecitabine and its nucleoside metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 783(1):273–285PubMedCrossRefGoogle Scholar
  28. 28.
    Besnard T, Renée N, Etienne-Grimaldi MC, François E, Milano G (2008) Optimized blood sampling with cytidine deaminase inhibitor for improved analysis of capecitabine metabolites. J Chromatogr B Analyt Technol Biomed Life Sci 870(1):117–120PubMedCrossRefGoogle Scholar
  29. 29.
    Rudek MA, Zhao M, He P, Hartke C, Gilbert J, Gore SD et al (2005) Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies. J Clin Oncol 23(17):3906–3911PubMedCrossRefGoogle Scholar
  30. 30.
    Laheru D, Croghan G, Bukowski R, Rudek M, Messersmith W, Erlichman C et al (2008) A phase I study of EKB-569 in combination with capecitabine in patients with advanced colorectal cancer. Clin Cancer Res 14(17):5602–5609PubMedCrossRefGoogle Scholar
  31. 31.
    Soepenberg O, Dumez H, Verweij J, Semiond D, deJonge MJ, Eskens FA et al (2005) Phase I and pharmacokinetic study of oral irinotecan given once daily for 5 days every 3 weeks in combination with capecitabine in patients with solid tumors. J Clin Oncol 23(4):889–898PubMedCrossRefGoogle Scholar
  32. 32.
    Pronk LC, Vasey P, Sparreboom A, Reigner B, Planting AS, Gordon RJ et al (2000) A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours. Br J Cancer 83:22–29PubMedCrossRefGoogle Scholar
  33. 33.
    Parikh PJ, Mahasittiwat P, Flexhman JW, Tan B, Mutch MG, Myerson RJ et al (2009) Predictors of complete pathologic response on a prospective locally advanced rectal cancer trial. J Clin Oncol Abst 453. Proceedings of ASCO Gastrointestinal Cancer SymposiumGoogle Scholar
  34. 34.
    Zhang Z, Shi Q, Sturgis EM, Spitz MR, Hong WK, Wei Q (2004) Thymidylate synthase 5′ and 3′-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck. Clin Cancer Res 10:7903–7910PubMedCrossRefGoogle Scholar
  35. 35.
    Ulrich CM, Curtin K, Potter JD, Bigler J, Caan B, Slattery ML (2005) Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 14:2509–2516PubMedCrossRefGoogle Scholar
  36. 36.
    Shi Q, Zhang A, Neumann AS, Li G, Spitz MR, Wei Q (2005) Case-control analysis of thymidylate synthase polymorphisms and risk of lung cancer. Carcinogenesis 26:649–656PubMedCrossRefGoogle Scholar
  37. 37.
    Javle MM, Okazaki T, Wolff RA, Varadhachary G, Ho L, Crane CH et al (2008) Combined effect of single nucleotide polymorphisms (SNPs) of gemcitabine metabolic genes on pancreatic cancer survival and drug toxicity. J Clin Oncol Abst 126. Proceedings ASCO Gastrointestinal Cancers SymposiumGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Colin D. Weekes
    • 1
  • Sujatha Nallapareddy
    • 1
  • Michelle A. Rudek
    • 2
  • Alexis Norris-Kirby
    • 2
  • Daniel Laheru
    • 2
  • Antonio Jimeno
    • 1
  • Ross C. Donehower
    • 2
  • Kathleen M. Murphy
    • 2
  • Manuel Hidalgo
    • 2
  • Sharyn D. Baker
    • 3
  • Wells A. Messersmith
    • 1
  1. 1.University of Colorado Cancer CenterAuroraUSA
  2. 2.Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  3. 3.Department of Pharmaceutical SciencesSt. Judes Children’s Research HospitalMemphisUSA

Personalised recommendations