Phase I study of doxorubicin, ICRF-187 and granulocyte/macrophage-colony-stimulating factor

  • Christina Walsh
  • Ronald H. Blum
  • Ruth Oratz
  • Alec Goldenberg
  • Andrea Downey
  • James L. Speyer
Original Papers Clinical Oncology
Received:
Accepted:

Summary

A group of 16 patients with advanced malignancy were entered on a phase I trial of escalating doses of doxorubicin with ICRF-187 for cardioprotection and granulocyte/macrophage-colony-stimulating factor (GMCSF) for bone marrow protection. Patients received intravenous ICRF-187 (dose ratio 20∶1 ICRF-187: doxorubicin) 30 min prior to doxorubicin. GMCSF at a dose of 15 μg kg−1 day−1 was self-administered subcutaneously on days 3–14 of the cycle. Doxorubicin was administered every 21 days. Substantial hematological and non-hematological toxicity was seen. Fever, malaise, and pulmonary symptoms, thought to be due to GMCSF, were not eliminated by reduction in the GMCSF dose to 10 or 5 μg kg−1 day−1. Severe hematological toxicity was seen despite GMCSF administration and it was not possible to escalate the doxorubicin dose above 72 mg/m2 with this combination. Dose escalation of doxorubicin may be more feasible with the use of other growth factors or growth factor combinations.

Key words

Doxorubicin GMCSF Dose escalation 

Abbreviations

GMCSF

granulocyte/macrophage-colony-stimulating factor

ICRF-187

(±)-1,2-bis(3,5-dioxopiperazinyl-1-yl)-propane

CMF

cyclophosphamide/methotrexate/5-fluorouracil

FDC

5-fluorouracil/doxorubicin/cyclophosphamide

ANC

absolute neutruophil count

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References

  1. 1.
    Antman K, Griffin J, Elias A et al. (1988) Effect of rhGMCSF on chemotherapy induced myelosuppression. N Engl J Med 319:593–598PubMedGoogle Scholar
  2. 2.
    Bonadonna G, Valagussa P (1981) Dose response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 304:10–15PubMedGoogle Scholar
  3. 3.
    Bronchud MH, Howell A, Crowther D, Hopwood P, Soza L, Dexter TM (1989) The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer 60:121–125PubMedGoogle Scholar
  4. 4.
    Doroshow J, Locker G, Myers C (1980) Enzymic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubin. JCI 65:128–135PubMedGoogle Scholar
  5. 5.
    Filippi J, Imandi A, Wolgemuth R (1987) Characterization of the cardioprotective effect of ICRF 187 on anthracycline cardiotoxicity. In: Hacker M, Lazo J, Tritton T (eds) Organ directed toxicities of anticancer drugs. Nijhoff, Boston, p 225Google Scholar
  6. 6.
    Gabrilove J, Jakubowski A, Scher H et al. (1988) Effect of GCSF on neutropenia and associated morbidity due to chemotherapy for TTC of the urothelium. N Engl J Med 318:1414–1422PubMedGoogle Scholar
  7. 7.
    Herman E, Mhatre R, Chadwick D (1974) Modification of some of the toxic effects of daunomycin (NSC-62161) by pretreatment with the antineoplastic agent ICRF-159 (NSC-129943). Toxicol Appl Pharmacol 27:517–526PubMedGoogle Scholar
  8. 8.
    Herman EH, Ferrans VJ, Jordan W, Adralan B (1981) Reduction of chronic daunorubicin cardiotoxicity by ICRF-187 in rabbits. Res Commun Chem Pathol Pharmacol 31:85–97PubMedGoogle Scholar
  9. 9.
    Herman EH, Ferrans VJ (1981) Reducation of chronic doxorubicin cardiotoxicity in dogs by pretreatment with (±)-1,2-bis(3,5-dioxopiperazinyl-1-yl) propane (ICRF-187). Cancer Res 41:3436–3440PubMedGoogle Scholar
  10. 10.
    Hortobagyi G, Bodey G, Buzdar H et al. (1987) Evaluation of high-dose versus standard dose FAC chemotherapy for advanced breast cancer in protected environment units: a prospective randomized study. J Clin Oncol 5:354–364PubMedGoogle Scholar
  11. 11.
    Hryniuk W, Figueredo A, Goodyear M (1987) Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol 14[Suppl 4]:3–11PubMedGoogle Scholar
  12. 12.
    Jones R, Holland F, Bhardwaj S et al. (1987) A Phase I–II study of intensive dose adriamycin for advanced breast cancer. J Clin Oncol 5:172–177PubMedGoogle Scholar
  13. 13.
    Lieschke G, Maher D, Cebon J et al. (1989) Effects of bacterially synthesized rh GMCSF in patients with advanced malignancy. Ann Int Med 110:357–364PubMedGoogle Scholar
  14. 14.
    Speyer JL, Green MD, Kramer EL, Rey M, Sanger J, Ward C, Dubin N, Ferrans V, Stecy P, Zeleniuch-Jacquotte A, Wernz J, Feit F, Meyers M, Slater W, Taubes S, Blum R, Muggia F (1988) Protective effect of ICRF-187 against chronic doxorubicin induced cardiac toxicity in women with advances breast cancer. N Engl J Med 319:745–752PubMedGoogle Scholar
  15. 15.
    Tannock I, Boyd N, DeBouer G et al. (1988) A randomized trial of two dose levels of cyclophosphamide, methotrexate and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 6:1377–1388PubMedGoogle Scholar
  16. 16.
    Vogel C, Gorowski E, Devila E et al. (1987) Phase I clinical trial and pharmacokinetics of weekly ICRF-187 infusion in patients with solid tumor. Drugs 5:187–198Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Christina Walsh
    • 1
  • Ronald H. Blum
    • 1
  • Ruth Oratz
    • 1
  • Alec Goldenberg
    • 1
  • Andrea Downey
    • 1
  • James L. Speyer
    • 1
  1. 1.Kaplan Cancer CenterNew York University Medical CenterNew YorkUSA

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