Advertisement

Investigational New Drugs

, Volume 31, Issue 5, pp 1345–1354 | Cite as

Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study

  • David M. Hyams
  • Arlene Chan
  • Celia de Oliveira
  • Raymond Snyder
  • Jeferson Vinholes
  • M. William Audeh
  • Victor M. Alencar
  • Janine Lombard
  • Bijoyesh Mookerjee
  • John Xu
  • Kathryn Brown
  • Paula KleinEmail author
PHASE II STUDIES

Summary

Hormone receptor-positive breast cancer is treated with estrogen inhibitors. Fulvestrant (FASLODEX™), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER. Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists. Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors. This randomized Phase II study evaluated cediranib plus fulvestrant. Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK). Patients received cediranib 45 mg/day (n = 31) or placebo (n = 31) both plus fulvestrant. Demographic/baseline characteristics were well balanced. Patients treated with cediranib had a numerical advantage in PFS (hazard ratio = 0.867, P = 0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant. CBR was 42 % in both arms. The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %). The incidence of grade ≥3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm. There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK. Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated. Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered.

Keywords

Hormone-sensitive Breast cancer Cediranib Fulvestrant 

Notes

Acknowledgments

Funding for this study was provided by AstraZeneca. We thank Dr Helen Jones, from Mudskipper Bioscience, who provided medical writing assistance funded by AstraZeneca.

Conflicts of interest

D.M.H. has received research funding from AstraZeneca, consulting income and honoraria from Genomic Health, research funding and honoraria from Centocor Ortho Biotec, and honoraria from Genentech. P.K. received remuneration for an advisory board for Genentech. J.V. was a member of an AstraZeneca advisory board. M.W.A. has received consultancy fees and research funding from AstraZeneca. J.L. received honoraria from AstraZeneca. B.M. was employed by AstraZeneca and owns stock in the company. J.X. and K.B. are employees of AstraZeneca and own stock in the company. All other authors declared no conflicts of interest.

References

  1. 1.
    GLOBOCAN statistics. 2008. Available at: https://doi.org/globocan.iarc.fr/.
  2. 2.
    Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P (2005) Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 104:1742–1750CrossRefGoogle Scholar
  3. 3.
    Wilcken N, Dear R (2008) Chemotherapy in metastatic breast cancer: A summary of all randomised trials reported 2000–2007. Eur J Cancer 44:2118–2225CrossRefGoogle Scholar
  4. 4.
    Cleator SJ, Ahamed E, Coombes RC, Palmieri C (2009) A 2009 update on the treatment of patients with hormone receptor-positive breast cancer. Clin Breast Cancer Suppl 1:S6–S17CrossRefGoogle Scholar
  5. 5.
    Addo S, Yates RA, Laight A (2002) A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers. Br J Cancer 87:1354–1359CrossRefGoogle Scholar
  6. 6.
    Morris C, Wakeling A (2002) Fulvestrant (‘Faslodex’)–a new treatment option for patients progressing on prior endocrine therapy. Endocr Relat Cancer 9:267–276CrossRefGoogle Scholar
  7. 7.
    Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, Kleeberg UR, Come SE, Vergote I, Gertler S, Buzdar A, Webster A, Morris C (2003) Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer 98:229–238CrossRefGoogle Scholar
  8. 8.
    Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Come SE, Osborne CK, Robertson JF (2005) Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: A prospectively planned combined survival analysis of two multicenter trials. Cancer 104:236–239CrossRefGoogle Scholar
  9. 9.
    Massarweh S, Schiff R (2007) Unraveling the mechanisms of endocrine resistance in breast cancer: New therapeutic opportunities. Clin Cancer Res 13:1950–1954CrossRefGoogle Scholar
  10. 10.
    Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R (2000) Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 18:1423–1431CrossRefGoogle Scholar
  11. 11.
    Foekens JA, Peters HA, Grebenchtchikov N, Look MP, Meijer-Van Gelder ME, Geurts-Moespot A, van der Kwast TH, Sweep CG, Klijn JG (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61:5407–5414PubMedGoogle Scholar
  12. 12.
    Rydén L, Linderbolm B, Nielsen NH, Emdin S, Jönsson PE, Landberg G (2003) Tumor specific VEGF-A and VEGFR2/KDR protein are co-expressed in breast cancer. Breast Cancer Res Treat 82:147–154CrossRefGoogle Scholar
  13. 13.
    Rydén L, Stendahl M, Jonsson H, Emdin S, Bengtsson NO, Landberg G (2005) Tumor-specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up. Implication of a link between VEGF pathway and tamoxifen response. Breast Cancer Res Treat 89:135–143CrossRefGoogle Scholar
  14. 14.
    Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676CrossRefGoogle Scholar
  15. 15.
    Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jürgensmeier JM, Ogilvie DJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400CrossRefGoogle Scholar
  16. 16.
    Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, Harder J, Blum H, Robertson J, Jürgensmeier JM, Puchalski TA, Young H, Saunders O, Unger C (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:3045–3054CrossRefGoogle Scholar
  17. 17.
    Yamamoto N, Tamura T, Yamamoto N, Yamada K, Yamada Y, Nokihara H, Fujiwara Y, Takahashi T, Murakami H, Boku N, Yamazaki K, Puchalski TA, Shin E (2009) Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 64:1165–1172CrossRefGoogle Scholar
  18. 18.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95CrossRefGoogle Scholar
  19. 19.
    Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C, Berkenblit A, Campos S, Horowitz N, Cannistra SA, Lee H, Lee J, Roche M, Hill M, Whalen C, Sullivan L, Tran C, Humphreys BD, Penson RT (2009) Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 27:5601–5606CrossRefGoogle Scholar
  20. 20.
    Fiedler W, Mesters R, Heuser M, Ehninger G, Berdel WE, Zirrgiebel U, Robertson JD, Puchalski TA, Collins B, Jurgensmeier JM, Serve H (2010) An open-label, Phase I study of cediranib (RECENTIN) in patients with acute myeloid leukemia. Leuk Res 34:196–202CrossRefGoogle Scholar
  21. 21.
    Langenberg MH, van Herpen CM, de Bono J, Schellens JH, Unger C, Hoekman K, Blum HE, Fiedler W, Drevs J, Le Maulf F, Fielding A, Robertson J, Voest EE (2009) Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of cediranib in patients with advanced solid tumors. J Clin Oncol 27:6152–6159CrossRefGoogle Scholar
  22. 22.
    Laurie SA, Gauthier I, Arnold A, Shepherd FA, Ellis PM, Chen E, Goss G, Powers J, Walsh W, Tu D, Robertson J, Puchalski TA, Seymour L (2008) Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. J Clin Oncol 26:1871–1878CrossRefGoogle Scholar
  23. 23.
    Chen E, Jonker D, Gauthier I, Maclean M, Wells J, Powers J, Seymour L (2009) Phase I study of cediranib in combination with oxaliplatin and infusional 5-fluorouracil in patients with advanced colorectal cancer. Clin Cancer Res 15:1481–1486CrossRefGoogle Scholar
  24. 24.
    Goss G, Shepherd FA, Laurie S, Gauthier I, Leighl N, Chen E, Feld R, Powers J, Seymour L (2009) A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer: A study of the National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 45:782–788CrossRefGoogle Scholar
  25. 25.
    Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D, Zukin M, Walde D, Laberge F, Vincent MD, Ellis PM, Laurie SA, Ding K, Frymire E, Gauthier I, Leighl NB, Ho C, Noble J, Lee CW, Seymour L (2010) Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol 28:49–55CrossRefGoogle Scholar
  26. 26.
    Liang Y, Brekken RA, Hyder SM (2006) Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 13:905–919CrossRefGoogle Scholar
  27. 27.
    Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M (2008) Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 26:1664–1670CrossRefGoogle Scholar
  28. 28.
    Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R, Buzdar A (2002) Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20:3386–3395CrossRefGoogle Scholar
  29. 29.
    Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko I, Khasanov R, Verhoeven D, Pedrini J, Lichinitser M, Pendergrass K, Garnett S, Lindemann J, Sapunar F, Martin M (2009) CONFIRM: Phase III, randomized, parallel-group trial comparing fulvestrant 250 mg vs fulvestrant 500 mg in postmenopausal women with oestrogen receptor-positive advanced breast cancer. Cancer Res 69(Suppl 3):25CrossRefGoogle Scholar
  30. 30.
    Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Rukazenkov Y, Martin M (2012) Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg. Cancer Res 72(24):S1–4Google Scholar
  31. 31.
    van Cruijsen H, Voest EE, Punt CJ, Hoekman K, Witteveen PO, Meijerink MR, Puchalski TA, Robertson J, Saunders O, Jürgensmeier JM, van Herpen CM, Giaccone G (2010) Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours. Eur J Cancer 46:901–911CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • David M. Hyams
    • 1
  • Arlene Chan
    • 2
  • Celia de Oliveira
    • 3
  • Raymond Snyder
    • 4
  • Jeferson Vinholes
    • 5
  • M. William Audeh
    • 6
  • Victor M. Alencar
    • 7
  • Janine Lombard
    • 8
  • Bijoyesh Mookerjee
    • 9
    • 12
  • John Xu
    • 9
  • Kathryn Brown
    • 10
  • Paula Klein
    • 11
    Email author
  1. 1.Desert Regional Medical Center Comprehensive Cancer CenterPalm SpringsUSA
  2. 2.Mount Medical CentrePerthAustralia
  3. 3.Instituto Brasileiro de Controle do CâncerSão PauloBrazil
  4. 4.St Vincent’s HospitalFitzroyAustralia
  5. 5.Clinionco-Unidade de Novos TratamentosPorto AlegreBrazil
  6. 6.Cedars-Sinai Outpatient Cancer CenterLos AngelesUSA
  7. 7.Centro Regional Integrado de OncologiaFortalezaBrazil
  8. 8.Newcastle Mater Misericordiae HospitalNewcastleAustralia
  9. 9.AstraZenecaWilmingtonUSA
  10. 10.AstraZenecaMacclesfieldUK
  11. 11.Beth Israel Medical Center and Continuum Cancer Centers of New YorkNew YorkUSA
  12. 12.IncyteWilmingtonUSA

Personalised recommendations