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Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas

  • Clinical Study - Patient Study
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Abstract

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m2/day and escalated by 25 mg/m2/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m2/day in the −EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. −EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m2/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.

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References

  1. Grossman SA, Levin V, Sawaya R, Maor M, Loeffler J (1997) National comprehensive cancer network adult brain tumor practice guidelines. Oncology 11:237–277

    Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  3. Costello PC, Del Maestro RF, Stetler-Stevenson WG (1994) Gelatinase A expression in human malignant gliomas. Ann N Y Acad Sci 732:450–452

    Article  PubMed  CAS  Google Scholar 

  4. Friedberg MH, Glantz MJ, Klempner MS, Cole BF, Perides G (1998) Specific matrix metalloproteinase profiles in the cerebrospinal fluid correlated with the presence of malignant astrocytomas, brain metastases, and carcinomatous meningitis. Cancer 82:923–930

    Article  PubMed  CAS  Google Scholar 

  5. Kachra Z, Beaulieu E, Delbecchi L, Mousseau N, Berthelet F, Moumdjian R, Del Maestro R, Beliveau R (1999) Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis 17:555–566

    Article  PubMed  CAS  Google Scholar 

  6. Sawaya RE, Yamamoto M, Gokaslan ZL, Wang SW, Mohanam S, Fuller GN, McCutcheon IE, Stetler-Stevenson WG, Nicolson GL, Rao JS (1996) Expression and localization of 72 kDa type IV collagenase (MMP-2) in human malignant gliomas in vivo. Clin Exp Metastasis 14:35–42

    Article  PubMed  CAS  Google Scholar 

  7. Wang M, Wang T, Liu S, Yoshida D, Teramoto A (2003) The expression of matrix metalloproteinase-2 and -9 in human gliomas of different pathological grades. Brain Tumor Pathol 20:65–72

    Article  PubMed  Google Scholar 

  8. Lu KV, Jong KA, Rajasekaran AK, Cloughesy TF, Mischel PS (2004) Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line. Lab Invest 84:8–20

    Article  PubMed  CAS  Google Scholar 

  9. Tonn JC, Kerkau S, Hanke A, Bouterfa H, Mueller JG, Wagner S, Vince GH, Roosen K (1999) Effect of synthetic matrix-metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in vitro. Int J Cancer 80:764–772

    Article  PubMed  CAS  Google Scholar 

  10. Nakabayashi H, Yawata T, Shimizu K (2010) Anti-invasive and antiangiogenic effects of MMI-166 on malignant glioma cells. BMC Cancer 10:339

    Article  PubMed  Google Scholar 

  11. Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, Rifkin BR (1991) Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 2:297–321

    PubMed  CAS  Google Scholar 

  12. Hidalgo M, Eckhardt SG (2001) Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 93:178–193

    Article  PubMed  CAS  Google Scholar 

  13. 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 19:584–592

    PubMed  CAS  Google Scholar 

  14. 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 10:6512–6521

    Article  PubMed  CAS  Google Scholar 

  15. Cianfrocca M, Cooley TP, Lee JY, Rudek MA, Scadden DT, Ratner L, Pluda JM, Figg WD, Krown 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 20:153–159

    Article  PubMed  CAS  Google Scholar 

  16. Chu QS, Forouzesh B, Syed S, Mita M, Schwartz G, Cooper J, Curtright J, Rowinsky EK (2007) A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest New Drugs 25:359–367

    Article  PubMed  CAS  Google Scholar 

  17. Ghate JV, Turner ML, 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 137:471–474

    PubMed  CAS  Google Scholar 

  18. Gilbert MR, Supko JG, Batchelor T, Lesser G, Fisher JD, Piantadosi S, Grossman S (2003) Phase I clinical and pharmacokinetic study of irinotecan in adults with recurrent malignant glioma. Clin Cancer Res 9:2940–2949

    PubMed  CAS  Google Scholar 

  19. Rudek MA, Hartke C, Zabelina Y, Zhao M, New P, Baker SD (2005) A sensitive method for determination of COL-3, a chemically modified tetracycline, in human plasma using high-performance liquid chromatography and ultraviolet detection. J Pharm Biomed Anal 37:751–756

    Article  PubMed  CAS  Google Scholar 

  20. 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 43:1124–1135

    Article  PubMed  CAS  Google Scholar 

  21. Li J, Zhou S, Huynh H, Chan E (2005) Significant intestinal excretion, one source of variability in pharmacokinetics of COL-3, a chemically modified tetracycline. Pharm Res 22:397–404

    Article  PubMed  Google Scholar 

  22. Li J, Huynh H, Chan E (2002) Evidence for dissolution rate-limited absorption of COL-3, a Matrix metalloproteinase inhibitor, leading to the irregular absorption profile in rats after oral administration. Pharm Res 19:1655–1662

    Article  PubMed  CAS  Google Scholar 

  23. Anderson GD (1998) A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 32:554–563

    Article  PubMed  CAS  Google Scholar 

  24. Sutherland L, Ebner T, Burchell B (1993) The expression of UDP-glucuronosyltransferases of the UGT1 family in human liver and kidney and in response to drugs. Biochem Pharmacol 45:295–301

    Article  PubMed  CAS  Google Scholar 

  25. Groves MD, Puduvalli VK, Conrad CA, Gilbert MR, Yung WK, Jaeckle K, Liu V, Hess KR, Aldape KD, Levin VA (2006) Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: a relationship among efficacy, joint toxicity and anticonvulsant status. J Neurooncol 80:83–90

    Article  PubMed  CAS  Google Scholar 

  26. Groves MD, Puduvalli VK, Hess KR, Jaeckle KA, Peterson P, Yung WK, Levin VA (2002) Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. J Clin Oncol 20:1383–1388

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

National Cancer Institute; National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland [U01-CA62475 to S.G; P30 CA006973].

Conflict of interest statement

None.

Author information

Author notes

  1. Surasak Phuphanich & Steven Piantadosi

    Present address: Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

Authors and Affiliations

  1. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA

    Pamela New

  2. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA

    Michelle A. Rudek, Steven Piantadosi, Joy D. Fisher & Stuart A. Grossman

  3. Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, 48202, USA

    Tom Mikkelsen

  4. Department of Hematology-Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA

    Surasak Phuphanich

  5. Department of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Jane B. Alavi

  6. Department of Neurology, University of Alabama, Birmingham, AL, 35294, USA

    Louis B. Nabors

  7. NABTT Central Office, Johns Hopkins University, 1550 Orleans St., CRB2-1M16, Baltimore, MD, 21231-1000, USA

    Stuart A. Grossman

Authors
  1. Michelle A. Rudek
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  2. Pamela New
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  3. Tom Mikkelsen
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  4. Surasak Phuphanich
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  5. Jane B. Alavi
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  7. Steven Piantadosi
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  8. Joy D. Fisher
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  9. Stuart A. Grossman
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Corresponding author

Correspondence to Stuart A. Grossman.

Additional information

This study is conducted for the New Approaches to Brain Tumor Therapy CNS Consortium

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Rudek, M.A., New, P., Mikkelsen, T. et al. Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas. J Neurooncol 105, 375–381 (2011). https://doi.org/10.1007/s11060-011-0602-9

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  • DOI: https://doi.org/10.1007/s11060-011-0602-9

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