Skip to main content

Advertisement

SpringerLink
Log in

A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy

  • Clinical Trial Report
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

Methods

Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.

Results

Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels −1 and −2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation ≥50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.

Conclusions

The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Abbreviations

CRC:

Colorectal cancer

HDACi:

Histone deacetylase inhibitor

TS:

Thymidylate synthase

5-FU:

5-Fluorouracil

LV:

Leucovorin

DLT:

Dose-limiting toxicity

MTD:

Maximum tolerated dose

PBMC:

Peripheral blood mononuclear cell

CBC:

Complete blood count

References

  1. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C et al (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147

    PubMed  CAS  Google Scholar 

  2. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041–1047

    Article  PubMed  CAS  Google Scholar 

  3. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544

    Article  PubMed  CAS  Google Scholar 

  4. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  PubMed  CAS  Google Scholar 

  5. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345

    Article  PubMed  CAS  Google Scholar 

  6. Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P et al (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914–4921

    Article  PubMed  CAS  Google Scholar 

  7. Longley DB, Harkin DP, Johnston PG (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338

    Article  PubMed  CAS  Google Scholar 

  8. Inoue T, Hibi K, Nakayama G, Komatsu Y, Fukuoka T, Kodera Y et al (2005) Expression level of thymidylate synthase is a good predictor of chemosensitivity to 5-fluorouracil in colorectal cancer. J Gastroenterol 40:143–147

    Article  PubMed  CAS  Google Scholar 

  9. Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, 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 55:1407–1412

    PubMed  CAS  Google Scholar 

  10. Shirota Y, Stoehlmacher J, Brabender J, Xiong YP, Uetake H, Danenberg KD et al (2001) ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 19:4298–4304

    PubMed  CAS  Google Scholar 

  11. Popat S, Matakidou A, Houlston RS (2004) Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 22:529–536

    Article  PubMed  CAS  Google Scholar 

  12. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F et al (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280:26729–26734

    Article  PubMed  CAS  Google Scholar 

  13. Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23

    Article  PubMed  CAS  Google Scholar 

  14. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A et al (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417:455–458

    Article  PubMed  CAS  Google Scholar 

  15. Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC (2005) Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 45:495–528

    Article  PubMed  CAS  Google Scholar 

  16. Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA et al (1998) A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci U S A 95:3003–3007

    Article  PubMed  CAS  Google Scholar 

  17. Richon VM, Garcia-Vargas J, Hardwick JS (2009) Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett 280:201–210

    Article  PubMed  CAS  Google Scholar 

  18. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12:1247–1252

    Article  PubMed  CAS  Google Scholar 

  19. Zhang W, Peyton M, Xie Y, Soh J, Minna JD, Gazdar AF et al (2009) Histone deacetylase inhibitor romidepsin enhances anti-tumor effect of erlotinib in non-small cell lung cancer (NSCLC) cell lines. J Thorac Oncol 4:161–166

    Article  PubMed  Google Scholar 

  20. Zhang QL, Wang L, Zhang YW, Jiang XX, Yang F, Wu WL et al (2009) The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis. Leukemia 23:1507–1514

    Article  PubMed  CAS  Google Scholar 

  21. Tumber A, Collins LS, Petersen KD, Thougaard A, Christiansen SJ, Dejligbjerg M et al (2007) The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo. Cancer Chemother Pharmacol 60:275–283

    Article  PubMed  CAS  Google Scholar 

  22. Lee JH, Park JH, Jung Y, Kim JH, Jong HS, Kim TY et al (2006) Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells. Mol Cancer Ther 5:3085–3095

    Article  PubMed  CAS  Google Scholar 

  23. Zhu WG, Otterson GA (2003) The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anti-Cancer Agents 3:187–199

    Article  CAS  Google Scholar 

  24. Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K (2003) Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 101:3236–3239

    Article  PubMed  CAS  Google Scholar 

  25. Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H et al (2003) Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2:971–984

    PubMed  CAS  Google Scholar 

  26. Pitts TM, Morrow M, Kaufman SA, Tentler JJ, Eckhardt SG (2009) Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models. Mol Cancer Ther 8:342–349

    Article  PubMed  CAS  Google Scholar 

  27. Fazzone W, Wilson PM, Labonte MJ, Lenz HJ, Ladner RD (2009) Histone deacetylase inhibitors suppress thymidylate synthase gene expression and synergize with the fluoropyrimidines in colon cancer cells. Int J Cancer 125:463–473

    Article  PubMed  CAS  Google Scholar 

  28. Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG, Davidsen SK (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2:151–163

    PubMed  CAS  Google Scholar 

  29. Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 97:10014–10019

    Article  PubMed  CAS  Google Scholar 

  30. Labonte MJ, Wilson PM, Fazzone W, Groshen S, Lenz HJ, Ladner RD (2009) DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines. BMC Med Genomics 2:67

    Article  PubMed  CAS  Google Scholar 

  31. 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 15:3223–3229

    PubMed  CAS  Google Scholar 

  32. Bonner RF, Emmert-Buck M, Cole K, Pohida T, Chuaqui R, Goldstein S et al. (1997) Laser capture microdissection: molecular analysis of tissue. Science 278:1481, 1483

    Google Scholar 

  33. Azuma M, Shi M, Danenberg KD, Gardner H, Barrett C, Jacques CJ et al (2007) Serum lactate dehydrogenase levels and glycolysis significantly correlate with tumor VEGFA and VEGFR expression in metastatic CRC patients. Pharmacogenomics 8:1705–1713

    Article  PubMed  CAS  Google Scholar 

  34. 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 15:3223–3229

    PubMed  CAS  Google Scholar 

  35. Lord RV, Salonga D, Danenberg KD, Peters JH, DeMeester TR, Park JM et al (2000) Telomerase reverse transcriptase expression is increased early in the Barrett’s metaplasia, dysplasia, adenocarcinoma sequence. J Gastrointest Surg 4:135–142

    Article  PubMed  CAS  Google Scholar 

  36. Koehler SE, Ladner RD (2004) Small interfering RNA-mediated suppression of dUTPase sensitizes cancer cell lines to thymidylate synthase inhibition. Mol Pharmacol 66:620–626

    PubMed  CAS  Google Scholar 

  37. Wilson PM, Fazzone W, LaBonte MJ, Deng J, Neamati N, Ladner RD (2008) Novel opportunities for thymidylate metabolism as a therapeutic target. Mol Cancer Ther 7:3029–3037

    Article  PubMed  CAS  Google Scholar 

  38. Fakih MG, Pendyala L, Egorin MJ, Fetterly G, Espinoza-Delgado I, Ross M et al (2009) A phase I clinical trial of vorinostat in combination with sFULV2 in patients with refractory solid tumors. J Clin Oncol 27:15 s (suppl; abstr 4083)

    Google Scholar 

  39. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK et al (2003) Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21:2059–2069

    Article  PubMed  CAS  Google Scholar 

  40. Fakih MG, Pendyala L, Fetterly G, Toth K, Zwiebel JA, Espinoza-Delgado I et al (2009) A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer. Clin Cancer Res 15:3189–3195

    Article  PubMed  CAS  Google Scholar 

  41. Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T et al (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923–3931

    Article  PubMed  CAS  Google Scholar 

  42. Kelly WK, Richon VM, O’Connor O, Curley T, MacGregor-Curtelli B, Tong W et al (2003) Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 9:3578–3588

    PubMed  CAS  Google Scholar 

  43. Marks PA, Breslow R (2007) Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 25:84–90

    Article  PubMed  CAS  Google Scholar 

  44. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N et al (2008) Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 409:581–589

    Article  PubMed  CAS  Google Scholar 

  45. Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F et al (2006) A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 12:4628–4635

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded by Merck & Co; NIH grant 5 P30CA14089-27I, the V Foundation for Cancer Research and the Dhont Family Foundation.

Author information

Authors and Affiliations

  1. Department of Pathology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

    Peter M. Wilson, William Fazzone, Melissa J. LaBonte, Margaret Kornacki & Robert D. Ladner

  2. Division of Medical Oncology, Sharon A. Carpenter Laboratory, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Room 5410, 1441 Eastlake Avenue, Los Angeles, CA, 90089, USA

    Anthony El-Khoueiry, Syma Iqbal, Sarah Cole & Heinz-Josef Lenz

  3. Biostatistics Core, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

    Susan Groshen & Dongyun Yang

  4. Response Genetics, Inc., Los Angeles, CA, 90033, USA

    Kathy D. Danenberg

Authors
  1. Peter M. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony El-Khoueiry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Syma Iqbal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William Fazzone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Melissa J. LaBonte
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susan Groshen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dongyun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kathy D. Danenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sarah Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Margaret Kornacki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Robert D. Ladner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Heinz-Josef Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heinz-Josef Lenz.

Additional information

Peter M. Wilson and Anthony El-Khoueiry contributed equally in the preparation of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilson, P.M., El-Khoueiry, A., Iqbal, S. et al. A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy. Cancer Chemother Pharmacol 65, 979–988 (2010). https://doi.org/10.1007/s00280-009-1236-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-009-1236-x

Keywords

Search

Navigation