Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jul;85(2):152–156. doi: 10.1054/bjoc.2001.1878

A phase II study of the bispecific antibody MDX-H210 (anti-HER2 × CD64) with GM-CSF in HER2+ advanced prostate cancer

N D James 1, P J Atherton 1, J Jones 1, A J Howie 2, S Tchekmedyian 3, R T Curnow 4
PMCID: PMC2364053  PMID: 11461069

Abstract

The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 μg m−2by intravenous infusion plus GM-CSF 5 μg kg−1day−1by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21–188) days. Toxicity was generally NCI-CTG 0–2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71–184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: prostate cancer, bispecific antibody, GM-CSF, HER2, immunotherapy

Full Text

The Full Text of this article is available as a PDF (62.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Connor R. I., Shen L., Fanger M. W. Evaluation of the antibody-dependent cytotoxic capabilities of individual human monocytes. Role of Fc gamma RI and Fc gamma RII and the effects of cytokines at the single cell level. J Immunol. 1990 Sep 1;145(5):1483–1489. [PubMed] [Google Scholar]
  2. Craft N., Shostak Y., Carey M., Sawyers C. L. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999 Mar;5(3):280–285. doi: 10.1038/6495. [DOI] [PubMed] [Google Scholar]
  3. Dawson N. A. Apples and oranges: building a consensus for standardized eligibility criteria and end points in prostate cancer clinical trials. J Clin Oncol. 1998 Oct;16(10):3398–3405. doi: 10.1200/JCO.1998.16.10.3398. [DOI] [PubMed] [Google Scholar]
  4. Fanger M. W., Morganelli P. M., Guyre P. M. Bispecific antibodies. Crit Rev Immunol. 1992;12(3-4):101–124. [PubMed] [Google Scholar]
  5. Fox S. B., Persad R. A., Coleman N., Day C. A., Silcocks P. B., Collins C. C. Prognostic value of c-erbB-2 and epidermal growth factor receptor in stage A1 (T1a) prostatic adenocarcinoma. Br J Urol. 1994 Aug;74(2):214–220. doi: 10.1111/j.1464-410x.1994.tb16589.x. [DOI] [PubMed] [Google Scholar]
  6. Guyre P. M., Graziano R. F., Vance B. A., Morganelli P. M., Fanger M. W. Monoclonal antibodies that bind to distinct epitopes on Fc gamma RI are able to trigger receptor function. J Immunol. 1989 Sep 1;143(5):1650–1655. [PubMed] [Google Scholar]
  7. Kallakury B. V., Sheehan C. E., Ambros R. A., Fisher H. A., Kaufman R. P., Jr, Muraca P. J., Ross J. S. Correlation of p34cdc2 cyclin-dependent kinase overexpression, CD44s downregulation, and HER-2/neu oncogene amplification with recurrence in prostatic adenocarcinomas. J Clin Oncol. 1998 Apr;16(4):1302–1309. doi: 10.1200/JCO.1998.16.4.1302. [DOI] [PubMed] [Google Scholar]
  8. Lyne J. C., Melhem M. F., Finley G. G., Wen D., Liu N., Deng D. H., Salup R. Tissue expression of neu differentiation factor/heregulin and its receptor complex in prostate cancer and its biologic effects on prostate cancer cells in vitro. Cancer J Sci Am. 1997 Jan-Feb;3(1):21–30. [PubMed] [Google Scholar]
  9. McLaughlin P., Grillo-López A. J., Link B. K., Levy R., Czuczman M. S., Williams M. E., Heyman M. R., Bence-Bruckler I., White C. A., Cabanillas F. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825–2833. doi: 10.1200/JCO.1998.16.8.2825. [DOI] [PubMed] [Google Scholar]
  10. Metcalf D. The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood. 1986 Feb;67(2):257–267. [PubMed] [Google Scholar]
  11. Morote J., de Torres I., Caceres C., Vallejo C., Schwartz S., Jr, Reventos J. Prognostic value of immunohistochemical expression of the c-erbB-2 oncoprotein in metastasic prostate cancer. Int J Cancer. 1999 Aug 20;84(4):421–425. doi: 10.1002/(sici)1097-0215(19990820)84:4<421::aid-ijc16>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  12. Peto R., Pike M. C., Armitage P., Breslow N. E., Cox D. R., Howard S. V., Mantel N., McPherson K., Peto J., Smith P. G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977 Jan;35(1):1–39. doi: 10.1038/bjc.1977.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Posey J. A., Raspet R., Verma U., Deo Y. M., Keller T., Marshall J. L., Hodgson J., Mazumder A., Hawkins M. J. A pilot trial of GM-CSF and MDX-H210 in patients with erbB-2-positive advanced malignancies. J Immunother. 1999 Jul;22(4):371–379. doi: 10.1097/00002371-199907000-00011. [DOI] [PubMed] [Google Scholar]
  14. Ross J. S., Nazeer T., Church K., Amato C., Figge H., Rifkin M. D., Fisher H. A. Contribution of HER-2/neu oncogene expression to tumor grade and DNA content analysis in the prediction of prostatic carcinoma metastasis. Cancer. 1993 Nov 15;72(10):3020–3028. doi: 10.1002/1097-0142(19931115)72:10<3020::aid-cncr2820721026>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  15. Ross J. S., Sheehan C., Hayner-Buchan A. M., Ambros R. A., Kallakury B. V., Kaufman R., Fisher H. A., Muraca P. J. HER-2/neu gene amplification status in prostate cancer by fluorescence in situ hybridization. Hum Pathol. 1997 Jul;28(7):827–833. doi: 10.1016/s0046-8177(97)90157-x. [DOI] [PubMed] [Google Scholar]
  16. Sadasivan R., Morgan R., Jennings S., Austenfeld M., Van Veldhuizen P., Stephens R., Noble M. Overexpression of Her-2/neu may be an indicator of poor prognosis in prostate cancer. J Urol. 1993 Jul;150(1):126–131. doi: 10.1016/s0022-5347(17)35413-7. [DOI] [PubMed] [Google Scholar]
  17. Slovin S. F., Scher H. I., Divgi C. R., Reuter V., Sgouros G., Moore M., Weingard K., Pettengall R., Imbriaco M., El-Shirbiny A. Interferon-gamma and monoclonal antibody 131I-labeled CC49: outcomes in patients with androgen-independent prostate cancer. Clin Cancer Res. 1998 Mar;4(3):643–651. [PubMed] [Google Scholar]
  18. Small E. J., Reese D. M., Um B., Whisenant S., Dixon S. C., Figg W. D. Therapy of advanced prostate cancer with granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 1999 Jul;5(7):1738–1744. [PubMed] [Google Scholar]
  19. Smith D. C., Dunn R. L., Strawderman M. S., Pienta K. J. Change in serum prostate-specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer. J Clin Oncol. 1998 May;16(5):1835–1843. doi: 10.1200/JCO.1998.16.5.1835. [DOI] [PubMed] [Google Scholar]
  20. Vollmer R. T., Dawson N. A., Vogelzang N. J. The dynamics of prostate specific antigen in hormone refractory prostate carcinoma: an analysis of cancer and leukemia group B study 9181 of megestrol acetate. Cancer. 1998 Nov 1;83(9):1989–1994. doi: 10.1002/(sici)1097-0142(19981101)83:9<1989::aid-cncr15>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  21. Yeh S., Lin H. K., Kang H. Y., Thin T. H., Lin M. F., Chang C. From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5458–5463. doi: 10.1073/pnas.96.10.5458. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES