Advertisement

Investigational New Drugs

, 25:359 | Cite as

A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas

  • Quincy S. C. ChuEmail author
  • Bahram Forouzesh
  • Samira Syed
  • Monica Mita
  • Garry Schwartz
  • Joshua Copper
  • Janet Curtright
  • Eric K. Rowinsky
Phase II Studies

Summary

This phase II study evaluated the antitumor activity of the tetracycline analog COL-3, a potent inhibitor of metalloproteinases (MMPs), particularly MMP-2 and MMP-9, on a continuous oral schedule at a dose of 50 mg/m2 daily in patients with advanced and/or metastatic soft tissue sarcoma (STS). The principal endpoints were the rate of objective tumor regression and the proportion of patients who did not experience disease progression during the first 8 weeks of treatment. Other study objectives included an assessment of pharmacology of COL-3, time to progression (TTP), and overall survival. A Simon two-stage design with multinomial stopping rule was employed, with 15 patients enrolled during the first stage of the study. Although COL-3 was generally well-tolerated, there were no objective responses and 5(33%) patients experienced disease progression during the first 8 weeks of treatment, which exceeded the criteria established a priori with regard to pursuing further evaluations of COL-3 in STS. The median values for TTP and survival were 109 and 279 days, respectively. Based on these results, further studies of COL-3 on this administration schedule in patients with STS are not warranted.

Keywords

Metalloproteinase inhibitor COL-3 Soft tissue sarcoma 

Abbreviations

MMP

Metalloproteinase

TTP

Time to progression

MMPI

Metalloproteinase inhibitor

STS

Soft tissue sarcomas

ECOG

Eastern Cooperative Group

CT

Computerized tomography

RECIST

Response evaluation criteria in solid tumours

HPLC

High-performance liquid chromatography

SD

Stable disease

PR

Partial response

CR

Complete response

HIV

Human Immunodeficiency Virus

Notes

Acknowledgments

The study was supported by a unrestricted grant from CollaGenex (Newton, PA).

References

  1. 1.
    Brennan MF, Alektiar KM, Maki RG (2001) Soft tissue sarcoma. In cancer: principles and practice of oncology, 6th ednGoogle Scholar
  2. 2.
    Bramwell VH, Anderson D, Charette ML, Sarcoma Disease Site Group (2003) Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatoc soft tissue sarcoma. Cochrane Database Syst Rev 3:CD003293PubMedGoogle Scholar
  3. 3.
    von Mehren M (2003) New therapeutic strategies for soft tissue sarcomas. Curr Treat Options Oncol 4:441–451PubMedGoogle Scholar
  4. 4.
    Hartmann JT, Patel S (2005) Recent developments in salvage chemotherapy for patients with metastatic soft tissue sarcoma. Drugs 65:167–178PubMedCrossRefGoogle Scholar
  5. 5.
    Liotta LA, Stetler-Stevenson WG (1990) Metalloproteinases and cancer. Semin Cancer Biol 1:99–106PubMedGoogle Scholar
  6. 6.
    Chambers AF, Matrisian L (1997) Changing view of the role of matrix metalloproteinases in metastases. J Natl Cancer Inst 89:1260–1270PubMedCrossRefGoogle Scholar
  7. 7.
    Hidalgo M, Eckhardt SG (2001) Development of Matrix Metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 93:178–193PubMedCrossRefGoogle Scholar
  8. 8.
    Jeffrey JJ (1991) Collagen and collagenase: pregnancy and parturition. Semin Perinatol 15:118–126PubMedGoogle Scholar
  9. 9.
    Talhouk R, Bisselm M, Werb Z (1992) Coordinated expression of extracellular matrix degrading proteinases and their inhibitors regulates mammary epithelial function during involution. J Cell Biol 118:1271–1282PubMedCrossRefGoogle Scholar
  10. 10.
    Gonzales-Avila G, Iturria C, Vadillo F, Teran L, Selman M, Perez-Tamayo R (1998) 72-kD (MMP-2) and 92 kD (MMP-9) type IV collagenase production and activity in different histologic types of lung cancer cells. Pathobiology 66:5–16CrossRefGoogle Scholar
  11. 11.
    Nawrocki B, Polette M, Marchand V, Monteau M, Gillery P, Tournier JM, Birembant P (1997) Expression of matrix metalloprotienases and their inhibitors in human bronchopulmonary carcinomas: quantitative and morphological analyses. Int J Cancer 72:556–564PubMedCrossRefGoogle Scholar
  12. 12.
    Hewitt RE, Leach IH, Powe DG, Clark IM, Cawston TE, Turner DR (1991) Distribution of collagenase and tissue inhibitor of metalloproteianses (TIMP) in colorectal tumors. Int J Cancer 49:666–672PubMedCrossRefGoogle Scholar
  13. 13.
    Yoshimoto M, Itoh F, Yamamoto H, Hinoda Y, Imai K, Tachi A (1993) Expression of MMP-7 (PUMP-1) mRNA in human colorectal cancers. Int J Cancer 54:614–618PubMedCrossRefGoogle Scholar
  14. 14.
    Bramhall ER (1997) The matrix metalloproteinases and their inhibitors in pancreatic cancer. From molecular science to a clinical application. Int J Pancreatol 21:1–12PubMedGoogle Scholar
  15. 15.
    Dano K, Romer J, Nielsen B, Bjorn S, Pyke C, Rygaard J, Lund LR (1999) Cancer invasion and tissue remodeling- cooperation of protease systems and cell types. APMIS 107:120–127PubMedCrossRefGoogle Scholar
  16. 16.
    Uria A, Stahle-BAckdahl M, Seiki M, Feuyo A, Lopez-Otin C (1997) Regulation of colleganse-3 expression in human breast cancer is mediated by stromal-epithelial cell interaction. Cancer Res 57:4882–4888PubMedGoogle Scholar
  17. 17.
    Heppner KJ, Matrisian LM, Jensen RA, Rodgers WH (1996) Expression of most matrix metalloproteinases family members in breast cancer represents a tumor-induced host response. Am J Pathol 149:273–282PubMedGoogle Scholar
  18. 18.
    Airola K, Karonen T, Vaalamo M, Lehti K, Lohi J, Rariniemi AL, Keski-Oja J, Saarialho-Keve UK (1999) Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlated with the level of invasion in maliganant melanomas. Br J Cancer 80:733–74PubMedCrossRefGoogle Scholar
  19. 19.
    Murray GI, Duncan ME, O’Neil P, McKay JA, Melvin WT, Fothergine JE (1998) Matrix metalloproteinase-1 is associated with poor survival prognosis in oesophageal cancer. J Pathol 185:256–261PubMedCrossRefGoogle Scholar
  20. 20.
    Murray GI, Duncan ME, O’Neil P, Melvin WT, Fothergine JE (1996) Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer. Nat Med 2:4610462Google Scholar
  21. 21.
    Benassi MS, Magagnoli G, Ponticelli F, Pazzaglia L, Zanella L, Gamberi G, Ragazzini P, Ferrari C, Mercuri M, Picci P (2003) Tissue and serum loss of metalloproteinase inhibitors in high grade soft tissue sarcomas. Histol Histolpathol 18:1035–1040Google Scholar
  22. 22.
    Ahlen J, Larsson O, Enberg U, Brosjo O, Backdahl M (1998) EMMPRIN and MMP-2 mRNA are co-expressed in oft tissue sarcoma. Proc AACR 3852:567Google Scholar
  23. 23.
    King J, Zhao J, Clingan P, Morris D (2003) Randomised double blind placebo control study of adjuvant treatment with the metalloproteinase inhibitor, Marimastat in patients with inoperable colorectal hepatic metastases: significant survival advantage in patients with musculoskeletal side-effects. Anti-cancer Res 23:639–645Google Scholar
  24. 24.
    Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN, Zucker S, Davidson NE (2004) Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol 22:4683–4690PubMedCrossRefGoogle Scholar
  25. 25.
    Shepherd FA, Giaccone G, Seymour L, Debruyne C, Bezjak A, Hirsh A, Smylie M, Rubin S, Martins H, Lamont A, Krzakowski M, Sadura A, Zee B (2002) Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the national cancer institute of canada-clinical trials group and the european organization for research and treatment of cancer. J Clin Oncol 20:4434–4439PubMedCrossRefGoogle Scholar
  26. 26.
    Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dafenais M, Fielaas A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L, National Cancer Institute of Canada Clinical Trials Group (2003) Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastastic adenocarcinoma of the pancreas: a phase III trial of the National cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:3296–3302PubMedCrossRefGoogle Scholar
  27. 27.
    Bissett D, O’Byrne KJ, von Pawel J, Gatzameier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhnag MH, Collier MA, Shepherd FA (2005) Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small cell lung cancer. J Clin Oncol 23:842–849PubMedCrossRefGoogle Scholar
  28. 28.
    Leighl NB, Paz-Ares L, Douillard JY, Peschel C, Arnold A, Deipierre A, Santoro A, Betticher AC, Gatzemeier U, Jassen J, Crawford J, Tu D, Bezjak A, Humphrey JS, Voi M, Galbraith S, Hann K, Seymour L, Shepherd FA (2005) Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18. J Clin Oncol 23:2831–2839PubMedCrossRefGoogle Scholar
  29. 29.
    Miller KD, Saphner TJ, Waterhouse DM, Chen TT, Rush-Taylor A, Sparano JA, Wolff AC, Cobliegh MA, Galbraith S, Sledge GW (2004) A randomized phase II feasibility trial of BMS-275291 in patients with early stage breast cancer. Clin Cancer Res 10:1971–1975PubMedCrossRefGoogle Scholar
  30. 30.
    Rudek MA, Figg WD, Dyer V, Dahut W, Turner ML, Steinberg SM, Liewehr DJ, Kohler DR, Pluda JM, Reed E (2001) Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J Clin Oncol 19:584–592PubMedGoogle Scholar
  31. 31.
    Syed S, Takimoto C, Hidalgo M, Rizzo J, Kuhn JG, Hammond LA, Schwartz G, Tolcher A, Patnaik A, Eckhardt SG, Rowinsky EK (2004) A phase I and pharmacokinetic study of COL-3 (Metastat), an oral tetracycline derivative with potent matrix metalloproteinase and antitumor properties. Clin Cancer Res 10:6512–6521PubMedCrossRefGoogle Scholar
  32. 32.
    Cianfrocca M, Cooley TP, Lee JY, Rudek MA, Scadden DT, Ratner L, Pluda JM, Figg WD, Known SE, Dezube BJ (2002) Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: A phase I AIDS Malignancy Consortium Study. J Clin Oncol 20:153–159PubMedCrossRefGoogle Scholar
  33. 33.
    Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T (1998) Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 12:12–26PubMedGoogle Scholar
  34. 34.
    Hanemaaijer R, Visser H, Koolwijk P, Sprsa T, Salo T, Golub LM (1998) Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. Adv Dent Res 12:114–118PubMedCrossRefGoogle Scholar
  35. 35.
    Attur GM, Dave MN, Mohandas N, Patel IR, Abramson SB, Amin AR. Regulation of inflammatory mediators by tetracyclines. In: Nelson M, Hillen W, Greenwald RA (eds.) Tetracyclines in biology, chemistry and medicine, pp 295–310Google Scholar
  36. 36.
    Patel RN, Attur MG, Dave MN, Patel IV, Stuchin SA, Abramson SB, Amin AR (1999) A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production. J Immunol 163:3459–3467PubMedGoogle Scholar
  37. 37.
    Gu Y, Lee HM, Roemer EJ, Masacchia L, Golub LM, Simon SR (2001) Inhibition of tumor cell invasiveness by chemically modified tetracyclines. Current Medicinal Chem 8:261–270Google Scholar
  38. 38.
    Lokeshwar BL, Slezer MG, Zhu BQ, Boock NL, Golub LM (2002) Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. Int J Cancer 98:297–309PubMedCrossRefGoogle Scholar
  39. 39.
    Pruzanski W, Stefanski E, Vadas P, McNamara TF, Ramamurthy N, Golub LM (1998) Chemically modified non-antimicrobial tetracyclines inhibit activity of phospholipase A2. J Rheumatol 25:1807–1812PubMedGoogle Scholar
  40. 40.
    Selzer MG, Zhu B, Block NL, Lokeshwar BL (1999) CMT-3, a chemically modified tetracycline, inhibits bony metastases and delays the development of paraplegia in a rat model of prostate cancer. Ann NY Acad Sci 878:678–692PubMedCrossRefGoogle Scholar
  41. 41.
    Li J, Huynh H, Chan E (2002) Evidence of dissolution rate-limited absorption of COL-3, a matrix metalloproteinase inhibitor, leading to the irregular absorption profile in rats after oral administration. Pharm Res 19:1655–662PubMedCrossRefGoogle Scholar
  42. 42.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2002) 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 92:205–216CrossRefGoogle Scholar
  43. 43.
    Van Glabbeke M, Verweij J, Judson I, Neilsen OS, on behalf of the EORTC Sodt Tissue and Bone Sarcoma Group (2002) Progression-free rate as the principal end-point for phase II trials in soft tissue sarcomas. Eur J Cancer 38:543–549PubMedCrossRefGoogle Scholar
  44. 44.
    Zee B, Melnychuk D, Dancey J, Eusenhauer E (1999) Multinomial phase II cancer trials incorporating response and early progression. J Biopharm Stat 9:3510363CrossRefGoogle Scholar
  45. 45.
    Dent S, Zee B, Dancey J, Hananske A, Wanders J, Eisenhauer E (2001) Application of a new multinomial phase II stopping rule using response and early progression. J Clin Oncol 19:785–791PubMedGoogle Scholar
  46. 46.
    Shepard J (2002) Severe complication of a commonly prescribed drug: minocycline-induced lupus. J Am Board Fam Practice 15:239–241Google Scholar
  47. 47.
    Ghate JV, Turner MJ, Rudek MA, Figg WD, Dahut W, Dyer V, Pluda JM, Reed E (2001) Drug-induced lupus associated with COL-3: report of 3 cases. Arch Dermatol 137:471–474PubMedGoogle Scholar
  48. 48.
    Rudek MA, Venitz J, Ando Y, Reed E, Pluda JM, Figg WD (2003) Factors involved in the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer: clinical and experimental studies. J Clin Pharmacol 43:1124–1135PubMedCrossRefGoogle Scholar
  49. 49.
    Maquoi E, Munaut C, Colige A, Lambert C, Frankenne, Noel Agnes, Grmas F, Krell H-W, Foidart J-M (2002) Stimulation of matrix metalloproteinase-9 expression in human fribrosarcoma cells by synthetic matrix metalloproteinase inhibitors. Exp Cell Res 275:110–121PubMedCrossRefGoogle Scholar
  50. 50.
    Kruger A, Soeltl R, Sopov I, Kopitz C, Arlt M, Magdolen V, Harbeck N, Ganabacher B, Schmitt M (2001) Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis. Cancer Res 61:1272–1275PubMedGoogle Scholar
  51. 51.
    Nelson AR, Fingleton B, Rothenberg ML, Martisian LM (2000) Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 18:1135–1149PubMedGoogle Scholar
  52. 52.
    Mesri EA (1999) Inflammatory reactivation and angiogenicity of Kaposi's sarcoma-associated herpesvirus/HHV-8: A missing link in the pathogenesis of acquired immunodeficiency syndrome-associated Kaposi's sarcoma. Blood 93:4031–4033PubMedGoogle Scholar
  53. 53.
    Dezube BJ (2000) The role of HIV-1 in the pathogenesis of AIDS-related Kaposi's sarcoma: the importance of an inflammatory and angiogenic milieu. Semin Oncol 27:420–423PubMedGoogle Scholar
  54. 54.
    Dezube BJ, Krown SE, Lee JY, Bauer KS, Aboulafia DM (2006) Randomized phase II trial of metrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi's sarcoma: an AIDS malignancy consortium study. J Clin Oncol 24:138901394CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Quincy S. C. Chu
    • 1
    Email author
  • Bahram Forouzesh
    • 2
  • Samira Syed
    • 2
  • Monica Mita
    • 2
  • Garry Schwartz
    • 3
  • Joshua Copper
    • 2
  • Janet Curtright
    • 2
  • Eric K. Rowinsky
    • 2
  1. 1.Cross Cancer InstituteEdmontonCanada
  2. 2.Institute for Drug Development, Cancer Therapy and Research CenterUniversity of Texas Health Science CenterSan AntonioUSA
  3. 3.Brooke Army Medical CenterFort Sam HoustonUSA

Personalised recommendations