Skip to main content

Advertisement

SpringerLink
Log in

Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer.

Methods

Eligible women were treated with POH four times daily at 1,200–1,500 mg m−2 dose−1 on a 28-day cycle. Patients tolerating 1,200 mg m−2 day−1 four times daily after one cycle were dose-escalated to 1,500 mg/m2. The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations.

Results

Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m2. Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29–123 days). Median overall survival was 389 days (95% CI, 202–776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-β1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability.

Conclusions

Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.

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

Similar content being viewed by others

References

  1. Abrams JS, Vena DA, Baltz J, Adams J, Montello M, Christian M, Onetto N, Desmond-Hellmann S, Canetta R, Friedman MA et al (1995) Paclitaxel activity in heavily pretreated breast cancer: a national cancer institute treatment referral center trial. J Clin Oncol 13:2056–2065

    PubMed  CAS  Google Scholar 

  2. Ariazi EA, Satomi Y, Ellis MJ, Haag JD, Shi W, Sattler CA, Gould MN (1999) Activation of the transforming growth factor beta signaling pathway and induction of cytostasis and apoptosis in mammary carcinomas treated with the anticancer agent perillyl alcohol. Cancer Res 59:1917–1928

    PubMed  CAS  Google Scholar 

  3. Azzoli CG, Miller VA, Ng KK, Krug LM, Spriggs DR, Tong WP, Riedel ER, Kris MG (2003) A phase I trial of perillyl alcohol in patients with advanced solid tumors. Cancer Chemother Pharmacol 51:493–498

    PubMed  CAS  Google Scholar 

  4. Bailey HH, Levy D, Harris LS, Schink JC, Foss F, Beatty P, Wadler S (2002) A phase II trial of daily perillyl alcohol in patients with advanced ovarian cancer: eastern cooperative oncology group study E2E96. Gynecol Oncol 85:464–468

    Article  PubMed  CAS  Google Scholar 

  5. Bailey HH, Wilding G, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Simon K, Marnocha R, Holstein SA, Stewart J, Lewis KA, Hohl RJ (2004) A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days. Cancer Chemother Pharmacol 54:368–376

    Article  PubMed  CAS  Google Scholar 

  6. Bardon S, Foussard V, Fournel S, Loubat A (2002) Monoterpenes inhibit proliferation of human colon cancer cells by modulating cell cycle-related protein expression. Cancer Lett 181:187–194

    Article  PubMed  CAS  Google Scholar 

  7. Bardon S, Picard K, Martel P (1998) Monoterpenes inhibit cell growth, cell cycle progression, and cyclin D1 gene expression in human breast cancer cell lines. Nutr Cancer 32:1–7

    Article  PubMed  CAS  Google Scholar 

  8. Berchtold CM, Chen KS, Miyamoto S, Gould MN (2005) Perillyl alcohol inhibits a calcium-dependent constitutive nuclear factor-kappaB pathway. Cancer Res 65:8558–8566

    Article  PubMed  CAS  Google Scholar 

  9. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T (1999) Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485–93

    PubMed  CAS  Google Scholar 

  10. Broitman SA, Wilkinson Jt, Cerda S, Branch SK (1996) Effects of monoterpenes and mevinolin on murine colon tumor CT-26 in vitro and its hepatic “metastases” in vivo. Adv Exp Med Biol 401:111–130

    PubMed  CAS  Google Scholar 

  11. Burke YD, Stark MJ, Roach SL, Sen SE, Crowell PL (1997) Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol. Lipids 32:151–156

    Article  PubMed  CAS  Google Scholar 

  12. Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL (1995) Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol 13:2731–2736

    PubMed  CAS  Google Scholar 

  13. Chan NL, Wang H, Wang Y, Leung HY, Leung LK (2006) Polycyclic aromatic hydrocarbon-induced CYP1B1 activity is suppressed by perillyl alcohol in MCF-7 cells. Toxicol Appl Pharmacol 213:98–104

    Article  PubMed  CAS  Google Scholar 

  14. Chung BH, Lee HY, Lee JS, Young CY (2006) Perillyl alcohol inhibits the expression and function of the androgen receptor in human prostate cancer cells. Cancer Lett 236:222–228

    Article  PubMed  CAS  Google Scholar 

  15. Clark SS (2006) Perillyl alcohol induces c-Myc-dependent apoptosis in Bcr/Abl-transformed leukemia cells. Oncology 70:13–18

    Article  PubMed  CAS  Google Scholar 

  16. Clark SS, Perman SM, Sahin MB, Jenkins GJ, Elegbede JA (2002) Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest. Leukemia 16:213–222

    Article  PubMed  CAS  Google Scholar 

  17. Clark SS, Zhong L, Filiault D, Perman S, Ren Z, Gould M, Yang X (2003) Anti-leukemia effect of perillyl alcohol in Bcr/Abl-transformed cells indirectly inhibits signaling through Mek in a Ras- and Raf-independent fashion. Clin Cancer Res 9:4494–4504

    PubMed  CAS  Google Scholar 

  18. Crowell PL, Chang RR, Ren ZB, Elson CE, Gould MN (1991) Selective inhibition of isoprenylation of 21–26-kDa proteins by the anticarcinogen d-limonene and its metabolites. J Biol Chem 266:17679–17685

    PubMed  CAS  Google Scholar 

  19. Fazeny B, Zifko U, Meryn S, Huber H, Grisold W, Dittrich C (1996) Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel—a phase II study. Cancer Chemother Pharmacol 39:150–156

    Article  PubMed  CAS  Google Scholar 

  20. Gibaldi M, Perrier D (1982) Pharmacokinetics. Marcel Dekker, New York, pp 445–449

    Google Scholar 

  21. Gomez-Contreras PC, Hernandez-Flores G, Ortiz-Lazareno PC, Del Toro-Arreola S, Delgado-Rizo V, Lerma-Diaz JM, Barba-Barajas M, Dominguez-Rodriguez JR, Bravo Cuellar A (2006) In vitro induction of apoptosis in U937 cells by perillyl alcohol with sensitization by pentoxifylline: increased BCL-2 and BAX protein expression. Chemotherapy 52:308–315

    Article  PubMed  CAS  Google Scholar 

  22. Gregory WM, Smith P, Richards MA, Twelves CJ, Knight RK, Rubens RD (1993) Chemotherapy of advanced breast cancer: outcome and prognostic factors. Br J Cancer 68:988–995

    PubMed  CAS  Google Scholar 

  23. Haag JD, Gould MN (1994) Mammary carcinoma regression induced by perillyl alcohol, a hydroxylated analog of limonene. Cancer Chemother Pharmacol 34:477–483

    Article  PubMed  CAS  Google Scholar 

  24. Haag JD, Lindstrom MJ, Gould MN (1992) Limonene-induced regression of mammary carcinomas. Cancer Res 52:4021–4026

    PubMed  CAS  Google Scholar 

  25. He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE (1997) Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J Nutr 127:668–674

    PubMed  CAS  Google Scholar 

  26. Hudes GR, Szarka CE, Adams A, Ranganathan S, McCauley RA, Weiner LM, Langer CJ, Litwin S, Yeslow G, Halberr T, Qian M, Gallo JM (2000) Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies. Clin Cancer Res 6:3071–3080

    PubMed  CAS  Google Scholar 

  27. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  28. Jirtle RL, Haag JD, Ariazi EA, Gould MN (1993) Increased mannose 6-phosphate/insulin-like growth factor II receptor and transforming growth factor beta 1 levels during monoterpene-induced regression of mammary tumors. Cancer Res 53:3849–3852

    PubMed  CAS  Google Scholar 

  29. Kaplan E, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481

    Article  Google Scholar 

  30. Liu G, Oettel K, Bailey H, Ummersen LV, Tutsch K, Staab MJ, Horvath D, Alberti D, Arzoomanian R, Rezazadeh H, McGovern J, Robinson E, DeMets D, Wilding G (2003) Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer. Invest New Drugs 21:367–372

    Article  PubMed  CAS  Google Scholar 

  31. Loutrari H, Hatziapostolou M, Skouridou V, Papadimitriou E, Roussos C, Kolisis FN, Papapetropoulos A (2004) Perillyl alcohol is an angiogenesis inhibitor. J Pharmacol Exp Ther 311:568–575

    Article  PubMed  CAS  Google Scholar 

  32. Meadows SM, Mulkerin D, Berlin J, Bailey H, Kolesar J, Warren D, Thomas JP (2002) Phase II trial of perillyl alcohol in patients with metastatic colorectal cancer. Int J Gastrointest Cancer 32:125–128

    Article  PubMed  CAS  Google Scholar 

  33. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214

    Article  PubMed  CAS  Google Scholar 

  34. NCI Common Toxicity Criteria version 1.0. http://www.fda.gov/cder/cancer/toxicityframe.htm, accessed 14 May 2007

  35. Phillips LR, Malspeis L, Supko JG (1995) Pharmacokinetics of active drug metabolites after oral administration of perillyl alcohol, an investigational antineoplastic agent, to the dog. Drug Metab Dispos 23:676–680

    PubMed  CAS  Google Scholar 

  36. Qi C, Park JH, Gibbs TC, Shirley DW, Bradshaw CD, Ella KM, Meier KE (1998) Lysophosphatidic acid stimulates phospholipase D activity and cell proliferation in PC-3 human prostate cancer cells. J Cell Physiol 174:261–272

    Article  PubMed  CAS  Google Scholar 

  37. Rajesh D, Howard SP (2003) Perillyl alcohol mediated radiosensitization via augmentation of the Fas pathway in prostate cancer cells. Prostate 57:14–23

    Article  PubMed  CAS  Google Scholar 

  38. Rajesh D, Stenzel RA, Howard SP (2003) Perillyl alcohol as a radio-/chemosensitizer in malignant glioma. J Biol Chem 278:35968–35978

    Article  PubMed  CAS  Google Scholar 

  39. Reddy BS, Wang CX, Samaha H, Lubet R, Steele VE, Kelloff GJ, Rao CV (1997) Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 57:420–425

    PubMed  CAS  Google Scholar 

  40. Ren Z, Gould MN (1998) Modulation of small G protein isoprenylation by anticancer monoterpenes in in situ mammary gland epithelial cells. Carcinogenesis 19:827–832

    Article  PubMed  CAS  Google Scholar 

  41. Ripple GH, Gould MN, Arzoomanian RZ, Alberti D, Feierabend C, Simon K, Binger K, Tutsch KD, Pomplun M, Wahamaki A, Marnocha R, Wilding G, Bailey HH (2000) Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day. Clin Cancer Res 6:390–396

    PubMed  CAS  Google Scholar 

  42. Ripple GH, Gould MN, Stewart JA, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Pomplun M, Wilding G, Bailey HH (1998) Phase I clinical trial of perillyl alcohol administered daily. Clin Cancer Res 4:1159–1164

    PubMed  CAS  Google Scholar 

  43. Romero A, Rabinovich MG, Vallejo CT, Perez JE, Rodriguez R, Cuevas MA, Machiavelli M, Lacava JA, Langhi M, Romero Acuna L et al (1994) Vinorelbine as first-line chemotherapy for metastatic breast carcinoma. J Clin Oncol 12:336–341

    PubMed  CAS  Google Scholar 

  44. Sahin MB, Perman SM, Jenkins G, Clark SS (1999) Perillyl alcohol selectively induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed myeloid cell lines. Leukemia 13:1581–1591

    Article  PubMed  CAS  Google Scholar 

  45. Samaila D, Toy BJ, Wang RC, Elegbede JA (2004) Monoterpenes enhanced the sensitivity of head and neck cancer cells to radiation treatment in vitro. Anticancer Res 24:3089–3095

    PubMed  CAS  Google Scholar 

  46. Shi W, Gould MN (2002) Induction of cytostasis in mammary carcinoma cells treated with the anticancer agent perillyl alcohol. Carcinogenesis 23:131–142

    Article  PubMed  CAS  Google Scholar 

  47. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  48. Stark MJ, Burke YD, McKinzie JH, Ayoubi AS, Crowell PL (1995) Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol. Cancer Lett 96:15–21

    Article  PubMed  CAS  Google Scholar 

  49. Stayrook KR, McKinzie JH, Burke YD, Burke YA, Crowell PL (1997) Induction of the apoptosis-promoting protein Bak by perillyl alcohol in pancreatic ductal adenocarcinoma relative to untransformed ductal epithelial cells. Carcinogenesis 18:1655–1658

    Article  PubMed  CAS  Google Scholar 

  50. Stearns V, Coop A, Singh B, Gallagher A, Yamauchi H, Lieberman R, Pennanen M, Trock B, Hayes DF, Ellis MJ (2004) A pilot surrogate end point biomarker trial of perillyl alcohol in breast neoplasia. Clin Cancer Res 10:7583–7591

    Article  PubMed  CAS  Google Scholar 

  51. Valero V, Holmes FA, Walters RS, Theriault RL, Esparza L, Fraschini G, Fonseca GA, Bellet RE, Buzdar AU, Hortobagyi GN (1995) Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13:2886–2894

    PubMed  CAS  Google Scholar 

  52. Wagner JE, Huff JL, Rust WL, Kingsley K, Plopper GE (2002) Perillyl alcohol inhibits breast cell migration without affecting cell adhesion. J Biomed Biotechnol 2:136–140

    Article  PubMed  CAS  Google Scholar 

  53. Wiseman DA, Werner SR, Crowell PL (2007) Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21(Cip1) and p27(Kip1) in human pancreatic adenocarcinoma cells. J Pharmacol Exp Ther 320:1163–1170

    Article  PubMed  CAS  Google Scholar 

  54. Xu M, Floyd HS, Greth SM, Chang WC, Lohman K, Stoyanova R, Kucera GL, Kute TE, Willingham MC, Miller MS (2004) Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects. Toxicol Appl Pharmacol 195:232–246

    Article  PubMed  CAS  Google Scholar 

  55. Yuri T, Danbara N, Tsujita-Kyutoku M, Kiyozuka Y, Senzaki H, Shikata N, Kanzaki H, Tsubura A (2004) Perillyl alcohol inhibits human breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 84:251–260

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank our patients and their families for their contribution to the advancement of clinical breast cancer research. We thank Marcia Pomplun and Amy Dresen of the University of Wisconsin Carbone Cancer Center 3P Laboratory for their technical assistance with the perillyl alcohol and TGF-β1 assays. We are grateful to Bo Huang for his statistical assistance as well as to Amyé Tevaarwerk for proofreading the manuscript. This study was supported by National Institutes of Health grants R21 CA 72500 and P30 CA 14520 as well as NCRR grant MOI RR03186.

Author information

Authors and Affiliations

  1. University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue K4/6 CSC, Madison, WI, 53792, USA

    Howard H. Bailey, Steven Attia, Richard R. Love, Terri Fass, Rick Chappell, Kendra Tutsch, Linda Harris & James A. Stewart

  2. Gundersen HealthCare, LaCrosse, WI, USA

    Alcee Jumonville

  3. Waukesha Regional Cancer Center, Waukesha, WI, USA

    Richard Hansen

  4. Aurora Sinai Medical Center, Milwaukee, WI, USA

    Gary R. Shapiro

Authors
  1. Howard H. Bailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven Attia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard R. Love
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Terri Fass
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rick Chappell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kendra Tutsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Linda Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alcee Jumonville
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Richard Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gary R. Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. James A. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Howard H. Bailey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bailey, H.H., Attia, S., Love, R.R. et al. Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer. Cancer Chemother Pharmacol 62, 149–157 (2008). https://doi.org/10.1007/s00280-007-0585-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0585-6

Keywords

Search

Navigation