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Clinical phase I and pharmacokinetic trial of vinorelbine administered as single intravenous bolus every 21 days in cancer patients

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Summary

We have performed a high-dose clinical and pharmacokinetic trial with vinorelbine administered as a bolus injection every 21 days. The aim was to evaluate a schedule with longer treatment intervals than one week and to determine the toxicity pattern of such a schedule. A total of 13 patients (pts) with solid tumors (non-small-cell lung [3 pts], unknown primary [3 pts], mesothelioma [2 pts], colon/rectum, sarcoma, thyroid, head/neck and cervix [1 pt each]) were entered [9 male, 4 female, median age: 56 years (range: 37–69)]. Dose levels were 35, 40 and 45 mg/m2 with a total of 26 cycles administered. At 40 mg/m2, 2/6 pts developed grade 4 granulocytopenia. 1/1 pt at 45 mg/m2 developed a grade 4 leuko- and granulocytopenia. Non-hematological toxicities were mild to moderate. Neurologic toxicity except for constipation was mild. Constipation occurred at 35 mg/m2 in 1/6 pts WHO grade 4, at 40 mg/m2 in 2/6 pts WHO grade 3 and at 45 mg/m2 in 1/1 pt WHO grade 4 and was due to neurotoxicity. No objective antitumor response was observed. Vinorelbine pharmacokinetics were analysed in whole blood and plasma and were similar to previously published studies using ≤30 mg/m2. Our results confirm a high affinity of vinorelbine to corpuscular blood elements. We conclude that the MTD of vinorelbine administered once every 21 days as bolus injection is 40 mg/m2, the dose-limiting toxicities are constipation and granulocytopenia and the recommended dose for subsequent Phase II trials is 35 mg/m2.

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References

  1. Wright TL, Hurley J, Korst DR, Monto RW, Rohn RJ, Will JJ, Louis J: Vinblastine in neoplastic disease. Cancer Res 23: 169–179, 1963

    Google Scholar 

  2. Brugarolas A, Lacave AJ, Ribas A, Garcia Miralles MT: Vincristine (NSC 67574) in non-small cell bronchogenic carcinoma. Eur J Cancer 14: 501–505, 1978

    Google Scholar 

  3. Sörensen JB, Österlind K, Hansen HH: Vinca alkaloids in the treatment of non-small cell lung cancer. Cancer Treatment Reviews 14: 29–51, 1987

    Google Scholar 

  4. Schulman P, Budman DR, Vinciguerra V, Weiselberg L, Abrams S, Degnan T: Phase II study of divided-dose vinblastine in non-small cell bronchogenic carcinoma. Cancer Treatment Reports 66:171–172, 1982

    Google Scholar 

  5. Kosmidis HV, Bouhoutsou DO, Varvoutsi C, Papadatos J, Stefanidis CG, Vlachos P, Scardoutsou A, Kostakis A: Vincristince overdose: Experience with 3 patients. Pediatric Hematology and Oncology 8:171–178, 1991

    Google Scholar 

  6. Belpomme D, Schwarzenberg L, Bohu A, Dhermy D, Bernard JF, Le Rol A, Pujade-Lauraine E, Bayssas M, Bouderlique JR, Bernard PF: Administration de vincaleucoblastine à fortes doses dans le cancers de l'ovaire évolués. Rev franc Gynéc 74: 579–601, 1979

    Google Scholar 

  7. Binet S, Fellous A, Lataste H, Krikorian A, Couzinier JP, Meininger V: In situ analysis of the action of navelbine on various types of microtubules using immunofluorescence. Semin Oncol 16: 5–8, 1989

    Google Scholar 

  8. Mathé G, Reizenstein P: Phase I pharmocologic study of a new vinca alkaloid: Navelbine. Cancer Letters 27: 285–293, 1985

    Google Scholar 

  9. Besenval M, Delgado M, Demarez JP, Krikorian A: Safety and tolerance of navelbine in phase I–II clinical studies. Semin Oncol 16: 37–40, 1989

    Google Scholar 

  10. Depierre A, Lemarie E, Dabouis G, Gamier G, Jacoulet P, Dalphin JC: A phase II study of navelbine (vinorelbine) in the treatment of non-small-cell lung cancer. Am J Clin Oncol 14: 115–119, 1991

    Google Scholar 

  11. WHO. WHO handbook for reporting results of cancer treatment. Geneva: 1979

  12. Puozzo C, Ung HL: A new sensitive and reliable HPLC method for routine analysis of vinorelbine and deacetyl-vinorelbine in human plasma, whole blood and urine. J Chromatogr, submitted for publication 1995

  13. Jehl F, Debs J: Determination of navelbine and desacetylnavelbine in biological fluids by high-performance liquid chromatography. J Chromatogr 525: 225–233, 1990

    Google Scholar 

  14. Gralla RJ, Casper ES, Kelsen DP, Braun DW, Dukeman ME, Martini N, Young CW, Golbey RB: Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: A randomized trial investigating two dosage schedules. Ann Int Med 95: 414–420, 1981

    Google Scholar 

  15. Burris HA, Fields S: Summary of data from in vitro and phase I vinorelbine (navelbine) studies. Semin Oncol 21: 14–19, 1994

    Google Scholar 

  16. Eghbali H: Phase II study of vinorelbine (Navelbine) in previously treated Hodgkin's disease and non-Hodgkin's lymphomas. In: Pierre Fabre Oncology (ed) Navelbine (Vinorelbine) Update and New Trends. John Libbey Eurotext Ltd, 92120 Montrouge, France, 1991, 253-260

  17. Niitani H, Furuse K, Fukuoka M, Hasegawa K, Taguchi T: [Phase I clinical study on new vinca alkaloid derivative, KW-2307 (vinorelbine). KW-2307 Study Group]. Gan To Kagaku Ryoho 21: 177–187, 1994

    Google Scholar 

  18. Toussaint C, Izzo J, Spielmann M, Merle S, May Levin F, Armand JP, Lacombe D, Tursz T, Sunderland M, Chabot GG, Cvitkovic E: Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer. J Clin Oncol 12: 2102–2112, 1994

    Google Scholar 

  19. Jassem J, Karnicka Mlodkowska H, van Pottelsberghe C, van Glabbeke M, Noseda MA, Ardizzoni A, Gozzelino F, Planting A, van Zandwijk N: Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer Cooperative Group. Eur J Cancer 29A: 1720–1722, 1993

    Google Scholar 

  20. Fumoleau P, Delgado FM, Delozier T, Monnier A, Gil Delgado MA, Kerbrat P, Garcia Giralt E, Keiling R, Namer M, Closon MT, et al: Phase II trial of weekly intravenous vinorelbine in firt-line advanced breast cancer chemotherapy. J Clin Oncol 11: 1245–1252, 1993

    Google Scholar 

  21. Tominaga T, Nomura Y, Adachi I, Aoyama H, Nagao K, Mitsuyama S, Nakamura Y, Ogita M, Sano M, Takashima S, etal: [Late phase II study of KW-2307 in advanced or recurrent breast cancer. KW-2307 Cooperative Study Group (Breast Cancer Section)]. Gan To Kagaku Ryoho 21: 809–816, 1994

    Google Scholar 

  22. Furuse K, Ohta M, Fukuoka M, Kurita Y, Kobayashi K, Hasegawa K, Kimura I, Fujii M, Yoshida S, Kitamura S, et al: [Early phase II clinical study of KW-2307 in patients with lung cancer. Lung Cancer Section in KW-2307 Study Group]. Gan To Kagaku Ryoho 21: 785–793, 1994

    Google Scholar 

  23. Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G: Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol 12: 2094–2101, 1994

    Google Scholar 

  24. Furuse K, Kinuwaki E, Motomiya M, Nishiwaki H, Hasegawa K, Kobayashi K, Kurita Y, Ohta K, Fukuoka M, Nakajima S, et al: [Late phase II clinical study of KW-2307 in previously untreated patients with non-small cell lung cancer. KW-2307 Study Group (Lung Cancer Group)]. Gan To Kagaku Ryoho 21: 1941–1947, 1994

    Google Scholar 

  25. Twelves CJ, Dobbs NA, Curnow A, Coleman RE, Stewart AL, Tyrrell CJ, Canney P, Rubens RD: A phase II, multicentre, UK study of vinorelbine in advanced breast cancer. Br J Cancer 70: 990–993, 1994

    Google Scholar 

  26. Pinon G, Pinel MC, Goudier MJ, Coiffier B, Filippi MH, Goupil A, Roullet B, Facchini T, Mignot L, Tresca P, et al: [Study of vinorelbine (V) combined with hexamethylmelamine (H) (combination V-H) in adenocarcinoma of the ovary: results a phase I-IIA trial, NHO-88, of ARTAC “ovarian” group]. Bull Cancer Paris 78: 1119–1131, 1991

    Google Scholar 

  27. Berthaud P, Le Chevalier T, Ruffie P, Baldeyrou P, Arriagada R, Besson F, Tursz T: Phase I–II study of vinorelbine (Navelbine) plus cisplatin in advanced non-small cell lung cancer. Eur J Cancer 28A: 1863–1865, 1992

    Google Scholar 

  28. Gridelli C, De Placido S, Pepe R, Incoronato P, Airoma G, Rossi A, Palazzolo G, Bianco AR: Phase I study of epirubicin plus vinorelbine with or without G-CSF in advanced non-small cell lung cancer. Eur J Cancer 29A: 1729–1731, 1993

    Google Scholar 

  29. Baldini E, Tibaldi C, Chella A, Angeletti CA, Romanini A, Andrei A, Algeri R, Silvano G, Conte PF: Combination chemotherapy with vinorelbine, ifosfamide, and cisplatin: a phase II study in stage IIIB-IV non-small cell lung cancer. Semin Oncol 21: 12–15, 1994

    Google Scholar 

  30. Spielmann M, Dorval T, Turpin F, Antoine E, Jouve M, Maylevin F, Lacombe D, Rouesse J, Pouillart P, Tursz T, et al: Phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer. J Clin Oncol 12: 1764–1770, 1994

    Google Scholar 

  31. Vokes EE, Drinkard LC, Samuels BL, Hoffman PC, Watson S, Bitran JD, Haraf DJ, Ferguson MF, Golomb HM: A phase II study of cisplatin, 5-fluorouracil, and leucovorin augmented by vinorelbine (Navelbine) for advanced non-small cell lung cancer: rationale and study design. Semin Oncol 21: 79–83, 1994

    Google Scholar 

  32. Khayat D, Covelli A, Variol P, Benhamouda A, Jacques C, Bugat R: Phase I and pharmacokinetic study of intravenous (i.v.) vinorelbine (vrl) in patients (pts) with solid tumors. Proceedings of ASCO 14: 469, 1995

    Google Scholar 

  33. Agostara B, Gebbia V, Testa A, Cusimano MP, Gebbia N, Callari AM: Mitomycin “C” and vinorelbine as second line chemotherapy for metastatic breast carcinoma. Tumori 80:33–36, 1994

    Google Scholar 

  34. Rahmani R, Bruno R, Iliadis A, Favre R, Just S, Barbett JJ, Cano JP: Clinical pharmacokinetics of antitumor drug navelbine (5-noranhydrovinblastine). Cancer Res 47: 5796–5799, 1987

    Google Scholar 

  35. Bore P, Rahmani R, van Cantfort J, Focan C, Cano JP: Pharmacokinetics of a new anticancer drug, navelbine, in patients. Comparison study of radioimmunologic and radioactive determination methods. Cancer Chemother Pharmacol 23: 247–251, 1989

    Google Scholar 

  36. Rahmani R, Gueritte F, Martin F, Just S, Cano JP: Comparative pharmacokinetic of antitumor vinca alkaloids: intravenous bolus injection of navelbine and related alkaloids to cancer patients and rats. Cancer Chemother Pharmacol 16: 223–228, 1986

    Google Scholar 

  37. Jehl F, Quoix E, Leveque D, Pauli G, Breillout F, Krikorian A, Monteil H: Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography. Cancer Res 51: 2073–2076, 1991

    Google Scholar 

  38. Rowinski EK, Noe DA, Trump DL, Winer EP, Lucas VS, Wargin WA, Hohneker JA, Lubejko B, Sartorius SE, Ettinger DS, Donehower RC: Pharmacokinetic, bioavailability and feasability study of oral vinorelbine in patients with solid tumors. J Clin Oncol 12: 1754–1763, 1994

    Google Scholar 

  39. Marquet P, Lachatre G, Debord J, Eichler B, Bonnaud F, Nicot G: Pharmacokinetics of vinorelbine in man. Eur J Clin Pharmacol 42: 545–547, 1992

    Google Scholar 

  40. Urien S, Bree F, Breillout F, Bastian G, Krikorian A, Tillement JP: Vinorelbine high-affinity binding to human platelets and lymphocytes: distribution in human blood. Cancer Chemother Pharmacol 231–234, 1993

  41. Rowland M, Tozer TN: Clinical pharmacokinetics: concepts and applications. Lea & Febinger Ed; 1980

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Authors and Affiliations

  1. Division of Hematology and Oncology, Klinikum rechts der Isar der Technischen Universität München, München, Germany

    Tassilo Schilling, Bernhard Heinrich & Axel-R Hanauske (Deputy Chief)

  2. Universitätklinik Freiburg, Freiburg, Germany

    Heiner H. Fiebig

  3. Pharmacia/Farmitalia Freiburg, Freiburg, Germany

    Sandor Kerpel-Fronius & B. Winterhalter

  4. Pierre Fabre Oncologie, Boulogne, France

    Philipp Variol & Patricia Tresca

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  1. Tassilo Schilling
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Schilling, T., Fiebig, H.H., Kerpel-Fronius, S. et al. Clinical phase I and pharmacokinetic trial of vinorelbine administered as single intravenous bolus every 21 days in cancer patients. Invest New Drugs 14, 371–378 (1996). https://doi.org/10.1007/BF00180813

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