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Phase I/II trial of non-cytotoxic suramin in combination with weekly paclitaxel in metastatic breast cancer treated with prior taxanes

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Abstract

Purpose

Suramin, a polysulfonated naphthylurea, inhibits the actions of polypeptide growth factors including acidic and basic fibroblast growth factors (aFGF and bFGF), which confer broad spectrum chemotherapy resistance. We hypothesized that suramin at non-cytotoxic doses in combination with weekly paclitaxel would be well tolerated and demonstrate anti-tumor activity.

Methods

Women with metastatic breast cancer who had been previously treated with a taxane in the adjuvant or metastatic setting were eligible. The primary objective of the phase I was to determine the dose of intravenous (IV) weekly suramin that resulted in plasma concentrations between 10 and 50 umol/l over 8–48 h (or the target range) in combination with IV 80 mg/m2 of weekly paclitaxel. The primary objective of the phase II trial was to determine the anti-tumor activity of the dosing regimen defined in phase I. Therapy was continued until disease progression or development of unacceptable toxicity.

Results

Thirty-one patients were enrolled (9: phase I; 22: phase II). In phase I, no dose-limiting toxicities were observed. Pharmacokinetics during the first cycle showed suramin concentrations within the target range for 21 of 24 weekly treatments (88 %). In phase II, the objective response rate (ORR) was 23 % (95 % CI 8–45 %), the median progression-free survival was 3.4 months (95 % CI 2.1–4.9 months), and the median overall survival was 11.2 months (95 % CI 6.6–16.0 months).

Conclusions

Non-cytotoxic doses of suramin in combination with weekly paclitaxel were well tolerated. The efficacy was below the pre-specified criteria required to justify further investigation.

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References

  1. Song S, Wientjes MG, Gan Y, Au JL (2000) Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs. Proc Natl Acad Sci USA 97(15):8658–8663. doi:10.1073/pnas.140210697

    Article  PubMed  CAS  Google Scholar 

  2. Gan Y, Wientjes MG, Au JL (2006) Expression of basic fibroblast growth factor correlates with resistance to paclitaxel in human patient tumors. Pharm Res 23(6):1324–1331. doi:10.1007/s11095-006-0136-6

    Article  PubMed  CAS  Google Scholar 

  3. Zhang Y, Song S, Yang F, Au JL, Wientjes MG (2001) Nontoxic doses of suramin enhance activity of doxorubicin in prostate tumors. J Pharmacol Exp Ther 299(2):426–433

    PubMed  CAS  Google Scholar 

  4. Song S, Yu B, Wei Y, Wientjes MG, Au JL (2004) Low-dose suramin enhanced paclitaxel activity in chemotherapy-naive and paclitaxel-pretreated human breast xenograft tumors. Clin Cancer Res 10(18 Pt 1):6058–6065. doi:10.1158/1078-0432.CCR-04-0595

    Article  PubMed  CAS  Google Scholar 

  5. Song S, Wientjes MG, Walsh C, Au JL (2001) Nontoxic doses of suramin enhance activity of paclitaxel against lung metastases. Cancer Res 61(16):6145–6150

    PubMed  CAS  Google Scholar 

  6. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the United States, national cancer institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  PubMed  CAS  Google Scholar 

  7. Chen D, Song SH, Wientjes MG, Yeh TK, Zhao L, Villalona-Calero M, Otterson GA, Jensen R, Grever M, Murgo AJ, Au JL (2006) Nontoxic suramin as a chemosensitizer in patients: dosing nomogram development. Pharm Res 23(6):1265–1274. doi:10.1007/s11095-006-0165-1

    Article  PubMed  Google Scholar 

  8. Villalona-Calero MA, Blum JL, Jones SE, Diab S, Elledge R, Khoury P, Von Hoff D, Kraynak M, Moczygemba J, Kromelis P, Griffin T, Rowinsky EK (2001) A phase I and pharmacologic study of capecitabine and paclitaxel in breast cancer patients. Ann Oncol 12(5):605–614

    Article  PubMed  CAS  Google Scholar 

  9. Villalona-Calero MA, Otterson GA, Wientjes MG, Weber F, Bekaii-Saab T, Young D, Murgo AJ, Jensen R, Yeh TK, Wei Y, Zhang Y, Eng C, Grever M, Au JL (2008) Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study. Ann Oncol 19(11):1903–1909. doi:10.1093/annonc/mdn412

    Article  PubMed  CAS  Google Scholar 

  10. George S, Dreicer R, Au JJ, Shen T, Rini BI, Roman S, Cooney MM, Mekhail T, Elson P, Wientjes GM, Ganapathi R, Bukowski RM (2008) Phase I/II trial of 5-fluorouracil and a noncytotoxic dose level of suramin in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 6(2):79–85. doi:10.3816/CGC.2008.n.012

    Article  PubMed  CAS  Google Scholar 

  11. Eisenberger MA, Reyno LM (1994) Suramin. Cancer Treat Rev 20(3):259–273

    Article  PubMed  CAS  Google Scholar 

  12. Stein CA (1993) Suramin: a novel antineoplastic agent with multiple potential mechanisms of action. Cancer Res 53(10 Suppl):2239–2248

    PubMed  CAS  Google Scholar 

  13. Waltenberger J, Mayr U, Frank H, Hombach V (1996) Suramin is a potent inhibitor of vascular endothelial growth factor. A contribution to the molecular basis of its antiangiogenic action. J Mol Cell Cardiol 28(7):1523–1529. doi:10.1006/jmcc.1996.0142

    Article  PubMed  CAS  Google Scholar 

  14. Bowden CJ, Figg WD, Dawson NA, Sartor O, Bitton RJ, Weinberger MS, Headlee D, Reed E, Myers CE, Cooper MR (1996) A phase I/II study of continuous infusion suramin in patients with hormone-refractory prostate cancer: toxicity and response. Cancer Chemother Pharmacol 39(1–2):1–8

    Article  PubMed  CAS  Google Scholar 

  15. Dreicer R, Smith DC, Williams RD, See WA (1999) Phase II trial of suramin in patients with metastatic renal cell carcinoma. Invest New Drugs 17(2):183–186

    Article  PubMed  CAS  Google Scholar 

  16. Falcone A, Pfanner E, Cianci C, Danesi R, Brunetti I, Del Tacca M, Conte PF (1995) Suramin in patients with metastatic colorectal cancer pretreated with fluoropyrimidine-based chemotherapy. A phase II study. Cancer 75(2):440–443

    Article  PubMed  CAS  Google Scholar 

  17. Falcone A, Pfanner E, Brunetti I, Allegrini G, Lencioni M, Galli C, Masi G, Danesi R, Antonuzzo A, Del Tacca M, Conte PF (1998) Suramin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in metastatic colorectal cancer patients resistant to 5-FU + LV-based chemotherapy. Tumori 84(6):666–668

    PubMed  CAS  Google Scholar 

  18. Falcone A, Antonuzzo A, Danesi R, Allegrini G, Monica L, Pfanner E, Masi G, Ricci S, Del Tacca M, Conte P (1999) Suramin in combination with weekly epirubicin for patients with advanced hormone-refractory prostate carcinoma. Cancer 86(3):470–476. doi:10.1002/(SICI)1097-0142(19990801)86:3<470:AID-CNCR15>3.0.CO;2-7

    Article  PubMed  CAS  Google Scholar 

  19. Mirza MR, Jakobsen E, Pfeiffer P, Lindebjerg-Clasen B, Bergh J, Rose C (1997) Suramin in non-small cell lung cancer and advanced breast cancer. Two parallel phase II studies. Acta Oncol 36(2):171–174

    Article  PubMed  CAS  Google Scholar 

  20. Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O’Shaughnessy JA (2006) Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 24(27):4384–4390. doi:10.1200/JCO.2005.05.1383

    Article  PubMed  CAS  Google Scholar 

  21. Xin Y, Lyness G, Chen D, Song S, Wientjes MG, Au JL (2005) Low dose suramin as a chemosensitizer of bladder cancer to mitomycin C. J Urol 174(1):322–327. doi:10.1097/01.ju.0000161594.86931.ea

    Article  PubMed  CAS  Google Scholar 

  22. Villalona-Calero MA, Wientjes MG, Otterson GA, Kanter S, Young D, Murgo AJ, Fischer B, DeHoff C, Chen D, Yeh TK, Song S, Grever M, Au JL (2003) Phase I study of low-dose suramin as a chemosensitizer in patients with advanced non-small cell lung cancer. Clin Cancer Res 9(9):3303–3311

    PubMed  CAS  Google Scholar 

  23. Cristofanilli M, Broglio KR, Guarneri V, Jackson S, Fritsehe HA, Islam R, Dawood S, Reuben JM, Kau SW, Lara JM, Krishnamurthy S, Ueno NT, Hortobagyi GN, Valero V (2007) Circulating tumor cells in metastatic breast cancer: biologic staging beyond tumor burden. Clin Breast Cancer 7(6):471–479. doi:10.3816/CBC.2007.n.004

    Article  PubMed  Google Scholar 

  24. www.clinicaltrial.gov

  25. 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(26):2666–2676. doi:10.1056/NEJMoa072113

    Article  PubMed  CAS  Google Scholar 

  26. Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL (2009) Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol 27(30):4966–4972. doi:10.1200/JCO.2008.21.6630

    Article  PubMed  CAS  Google Scholar 

  27. Blum JL, Dees EC, Vukelja SJ, Amare M, Gill DP, McMahon RT, Ilegbodu D, Asmar L, O’Shaughnessy JA (2007) Phase II trial of capecitabine and weekly paclitaxel in patients with metastatic breast cancer previously treated with every-3-week taxane therapy. Clin Breast Cancer 7(6):465–470

    Article  PubMed  CAS  Google Scholar 

  28. Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, Vahdat LT, Bunnell CA, Burris HA, Viens P, Baselga J, Rivera E, Guarneri V, Poulart V, Klimovsky J, Lebwohl D, Martin M (2007) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 25(23):3399–3406. doi:10.1200/JCO.2006.08.9102

    Article  PubMed  CAS  Google Scholar 

  29. Walsh CT, Wei Y, Wientjes MG, Au JL (2008) Quantitative image analysis of intra-tumoral bFGF level as a molecular marker of paclitaxel resistance. J Transl Med 6:4. doi:10.1186/1479-5876-6-4

    Article  PubMed  Google Scholar 

  30. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11(16):5678–5685. doi:10.1158/1078-0432.CCR-04-2421

    Article  PubMed  CAS  Google Scholar 

  31. Andre F, Hatzis C, Anderson K, Sotiriou C, Mazouni C, Mejia J, Wang B, Hortobagyi GN, Symmans WF, Pusztai L (2007) Microtubule-associated protein-tau is a bifunctional predictor of endocrine sensitivity and chemotherapy resistance in estrogen receptor-positive breast cancer. Clin Cancer Res 13(7):2061–2067. doi:10.1158/1078-0432.CCR-06-2078

    Article  PubMed  CAS  Google Scholar 

  32. Stengel C, Newman SP, Leese MP, Potter BV, Reed MJ, Purohit A (2010) Class III beta-tubulin expression and in vitro resistance to microtubule targeting agents. Br J Cancer 102(2):316–324. doi:10.1038/sj.bjc.6605489

    Article  PubMed  CAS  Google Scholar 

  33. Chang H, Rha SY, Jeung HC, Im CK, Ahn JB, Kwon WS, Yoo NC, Roh JK, Chung HC (2009) Association of the ABCB1 gene polymorphisms 2677G > T/A and 3435C > T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients. Ann Oncol 20(2):272–277. doi:10.1093/annonc/mdn624

    Article  PubMed  CAS  Google Scholar 

  34. Marsh S, Somlo G, Li X, Frankel P, King CR, Shannon WD, McLeod HL, Synold TW (2007) Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer. Pharmacogenomics J 7(5):362–365. doi:10.1038/sj.tpj.6500434

    Article  PubMed  CAS  Google Scholar 

  35. Seidman AD, Hudis CA, Albanell J, Tong W, Tepler I, Currie V, Moynahan ME, Theodoulou M, Gollub M, Baselga J, Norton L (1998) Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16(10):3353–3361

    PubMed  CAS  Google Scholar 

  36. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R (2001) Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 19(22):4216–4223

    PubMed  CAS  Google Scholar 

  37. Lombardi D, Crivellari D, Scuderi C, Magri MD, Spazzapan S, Sorio R, Di Lauro V, Scalone S, Veronesi A (2004) Long-term, weekly one-hour infusion of paclitaxel in patients with metastatic breast cancer: a phase II monoinstitutional study. Tumori 90(3):285–288

    PubMed  CAS  Google Scholar 

  38. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C (2008) Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of cancer and Leukemia group B protocol 9840. J Clin Oncol 26(10):1642–1649. doi:10.1200/JCO.2007.11.6699

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by 3 P30 CA016058-33S2 Avon Foundation OSU Comprehensive Cancer Center Supplement and the K12 CA133250, Translational Training Grant in Expiremental Therapeutics. Au and Wientjes have been awarded patents on the use of suramin as a chemosensitizer.

Conflict of interest

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, B421 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210-1240, USA

    Maryam B. Lustberg, Shubham Pant, Amy S. Ruppert, Lisa Brenner, Donna Shiels, Rhonda R. Jensen, Ewa Mrozek, Bhuvaneswari Ramaswamy, Michael Grever & Charles L. Shapiro

  2. College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Tong Shen, Yong Wei, Ling Chen, Jessie L. Au & M. Guillaume Wientjes

  3. Department of Pharmacy, The Ohio State University Medical Center, Columbus, OH, USA

    Michael Berger

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  1. Maryam B. Lustberg
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  2. Shubham Pant
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Correspondence to Maryam B. Lustberg.

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Lustberg, M.B., Pant, S., Ruppert, A.S. et al. Phase I/II trial of non-cytotoxic suramin in combination with weekly paclitaxel in metastatic breast cancer treated with prior taxanes. Cancer Chemother Pharmacol 70, 49–56 (2012). https://doi.org/10.1007/s00280-012-1887-x

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  • DOI: https://doi.org/10.1007/s00280-012-1887-x

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