Advertisement

Annals of Surgical Oncology

, Volume 2, Issue 6, pp 550–556 | Cite as

Phase I/II dose-escalation study of liarozole in patients with stage D, hormone-refractory carcinoma of the prostate

  • E. James Seidmon
  • Donald L. Trump
  • Willi Kreis
  • Stephen W. Hall
  • Michael R. Kurman
  • S. Peter Ouyang
  • Jane Wu
  • Alton B. Kremer
Original Articles

Abstract

Background: Liarozole binds to the cytochrome P-450-dependent hydroxylating enzymes involved in steroid biosynthesis and retinoic acid catabolism. This phase I study investigated the clinical/endocrine toxicity profile of liarozole and determined the maximally tolerated dose (MTD) in hormone-refractory prostate cancer patients.

Methods: Groups of five patients were treated with oral liarozole caplets, starting at 37.5 mg twice daily. The dose was doubled for each subsequent group until the MTD was reached, after which, an additional 18 patients were entered into the MTD-1 dose stratum. The long-term safety of liarozole was assessed based on treatment-emergent signs and symptoms and clinically significant laboratory results.

Results: Thirty-eight patients were enrolled. The MTD was determined to be 300 mg twice daily. Side effects that defined the MTD included lethargy, somnolence, body rash, and paresthesias. Two deaths occurred during the trial (pneumonia and myocardial infarction). Four patients had a >50% decrease in prostate-specific antigen (PSA) levels (two at 150 mg, two at 300 mg). Of nine patients with measurable disease, two had partial responses.

Conclusions: Liarozole was generally well tolerated with no evidence of adrenal insufficiency. Preliminary evidence of activity in this indication was observed based on dose-dependent decreases in PSA levels and improvement in soft-tissue metastasis.

Key words

Liarozole Prostate Cancer Retinomodulator Benzimidizole Chemotherapy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    American Cancer Society. Cancer Statistics, 1993.CA Cancer J Clin 1993;43:7.Google Scholar
  2. 2.
    Boring CC, Squires TS, Tong T, Montgomery S. Cancer statistics, 1994.CA Cancer J Clin 1994;44:7–26.PubMedGoogle Scholar
  3. 3.
    Torti F. Approaches to chemotherapy of prostate cancer.Adv Oncol 1988;4:15.Google Scholar
  4. 4.
    Murphy GP, Slack NH, Karr JP. Natural history, staging, and grading of prostate cancer. In: Javadpour N, ed.Principles and management of urologic cancer. Baltimore: Williams & Wilkins, 1993:353.Google Scholar
  5. 5.
    Klein LA. Prostatic carcinoma.N Engl J Med 1979;300:824.PubMedGoogle Scholar
  6. 6.
    Veterans Administration Cooperative Urological Research Group. Treatment and survival of patients with cancer of the prostate.Surg Gynecol Obstet 1967;124:1011.Google Scholar
  7. 7.
    Lyss AP. Systemic treatment for prostate cancer.Am J Med 1987;83:1120.CrossRefPubMedGoogle Scholar
  8. 8.
    Eisenberger MA, Bezerdjian L, Kalash S. A critical assessment of the role of chemotherapy for endocrine resistant prostatic carcinoma.Urol Clin North Am 1987;14:695.PubMedGoogle Scholar
  9. 9.
    Trachtenberg J. Ketoconazole treatment of advanced prostatic cancer.Prostate 1984;5:324.Google Scholar
  10. 10.
    Trachtenberg J, Halpern N, Pont A. Ketoconazole: a novel and rapid treatment for advanced prostate cancer.J Urol 1983;130:152.PubMedGoogle Scholar
  11. 11.
    Trump DL, Havlin KH, Messing EM, et al. High-dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinological and clinical effects.J Clin Oncol 1989;7:1093.PubMedGoogle Scholar
  12. 12.
    Sella A, Kilbourn R, Bui C, et al. Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer.J Clin Oncol 1994;12:683.PubMedGoogle Scholar
  13. 13.
    Rochlitz CF, Damon LE, Russi MB, et al. Cytotoxicity of ketoconazole in malignant cell lines.Cancer Chemother Pharmacol 1988;21:319.CrossRefPubMedGoogle Scholar
  14. 14.
    Van Ginckel R, DeCoster R, Wouters W, et al. Antitumoral effects of R75251 on the growth to transplantable R3327 prostatic adenocarcinoma in rats.Prostate 1990;16:313.PubMedGoogle Scholar
  15. 15.
    End DW, Wouters W, Van Ginckel R, et al. R75251: an antitumoral agent which inhibits retinoic acid metabolism.Proc AACR 1991;32:213.Google Scholar
  16. 16.
    DeCoster R, Wouters W, Van Ginckel R, et al. Experimental studies with liarozole (R75,251): an antitumor agent which inhibits retinoic acid breakdown.J Steroid Biochem Mol Biol 1992;43:197.Google Scholar
  17. 17.
    Slack NH, Brady MF, Murphy GP, et al. A reexamination of the stable category for evaluating responses in patients with advanced prostate cancer.Cancer 1984;54:564.PubMedGoogle Scholar
  18. 18.
    Ritter MA, Messing EM, Shanahan TG, et al. Prostatespecific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer.J Clin Oncol 1992;10:1208.PubMedGoogle Scholar
  19. 19.
    Kelly WK, Scher HI, Mazumdar M, et al. Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer.J Clin Oncol 1993;11:607.PubMedGoogle Scholar
  20. 20.
    Kelly WK, Scher HI. Prostate-specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome.J Urol 1993;149:607.PubMedGoogle Scholar
  21. 21.
    Scher HI, Kelly WK. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer.J Clin Oncol 1993;11:1566.PubMedGoogle Scholar
  22. 22.
    Lasnitzki I. The influence of a hypervitaminosis on the effect of 20-methylcholanthrene on mouse prostate glands grown in vitro.Br J Cancer 1955;9:434.PubMedGoogle Scholar
  23. 23.
    Lasnitzki I. Hypovitaminosis-A in the mouse prostate gland cultured in chemically defined medium.Exp Cell Res 1962;28:40.CrossRefGoogle Scholar
  24. 24.
    Lippman SM, Parkinson DR, Itri LM, et al. 13-Cis-retinoic acid and interferon alpha 2a: effective combination therapy for advanced squamous cell carcinoma of the skin.J Natl Cancer Inst 1992;84:235.PubMedGoogle Scholar

Copyright information

© The Society of Surgical Oncology, Inc 1995

Authors and Affiliations

  • E. James Seidmon
    • 5
  • Donald L. Trump
    • 1
  • Willi Kreis
    • 2
  • Stephen W. Hall
    • 3
  • Michael R. Kurman
    • 4
  • S. Peter Ouyang
    • 4
  • Jane Wu
    • 4
  • Alton B. Kremer
    • 4
  1. 1.Department of MedicineDuke University Medical CenterDurhamUSA
  2. 2.Department of MedicineNorth Shore University HospitalManhassetUSA
  3. 3.Department of MedicineUniversity of Nevada Medical CenterRenoUSA
  4. 4.Janssen Research FoundationTitusvilleUSA
  5. 5.Department of UrologyTemple University HospitalPhiladelphiaUSA

Personalised recommendations