Skip to main content

Advertisement

SpringerLink
Log in

A phase I study of ZD0473 combined with paclitaxel for the treatment of solid malignancies

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

ZD0473 is a cytotoxic platinum agent, which in preclinical studies has exhibited synergistic activity when combined with paclitaxel. The aim of this open-label phase I study was to determine the maximum tolerated dose (MTD), safety, and antitumour activity of ZD0473 followed by paclitaxel in patients with refractory solid malignancies.

Methods

Patients received paclitaxel and ZD0473 on day 1 every 3 weeks. Seven dose levels were planned (ZD0473 60–180 mg/m2, paclitaxel 135–175 mg/m2), with dose escalation dependent on the incidence of dose-limiting toxicity.

Results

Included in the study were 23 patients who received 76 treatment cycles at dose levels 1 (60 mg/m2 ZD0473, 135 mg/m2 paclitaxel) to 6 (150 mg/m2 ZD0473, 175 mg/m2 paclitaxel). Dose-limiting thrombocytopenia (platelet count <25×109/l) occurred in two of six patients at dose level 6, which defined the MTD. Grade 3/4 haematological toxicities included: anaemia (21.7%), neutropenia (39.1%), thrombocytopenia (34.8%), and leucopenia (34.8%). The most common grade 3/4 non-haematological toxicities included: alopecia (13.0%), pleural effusion (13.0%), somnolence (8.7%), and vomiting (8.7%). Of the 23 patients, 11 (47.8%) had disease stabilization, including 4 with non-small-cell lung cancer (NSCLC) who had a ≥25% reduction in tumour dimensions.

Conclusions

ZD0473 combined with paclitaxel has a manageable tolerability profile and shows some evidence of antitumour activity in patients with NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Belani CP, Kearns CM, Zuhowski EG, Erkmen K, Hiponia D, Zacharski D, Engstrom C, Ramanathan RK, Capozzoli MJ, Aisner J, Egorin MJ (1999) Phase I trial, including pharmacokinetic and pharmacodynamic correlations of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer. J Clin Oncol 17:676–684

    CAS  PubMed  Google Scholar 

  2. Chabner BA, Horowitz SB, Clendennin NJ, Purvis JD (1991) Vinca alkaloids. Cancer Chemother Biol Response Modif 12:67–73

    CAS  PubMed  Google Scholar 

  3. du Bois A (2001) Treatment of advanced ovarian cancer. Eur J Cancer 37 [Suppl 9]:S1–7

    Google Scholar 

  4. Frasci G, Comella P, Parziale A, Casaretti R, Daponte A, Gravina A, De Rosa L, Gallipoli A, Comella G (1997) Cisplatin-paclitaxel weekly schedule in advanced solid tumours: a phase I study. Ann Oncol 8:291–293

    Article  CAS  PubMed  Google Scholar 

  5. Gore M, Atkinson RJ, Dirix L, Rischin D, Beale P, Harnet P, Hacking D, Cure H, Cosaert J (2001) ZD0473 phase II monotherapy trial in second-line ovarian cancer (abstract 967). Eur J Cancer 37 [Suppl 6):S261

  6. Hoctin-Boes G, Cosaert J, Koehler M, Smith M (2001) Safety profile of ZD0473 in phase II trials of patients with advanced cancers (abstract 1372). Proc Am Soc Clin Oncol 20:344

    Google Scholar 

  7. O'Dwyer PJ, Stevenson JP, Johnson SW (2000) Clinical pharmacokinetics and administration of established platinum drugs. Drugs 59 [Suppl 4]:19–27

  8. Perez RP (1998) Cellular and molecular determinants of cisplatin resistance. Eur J Cancer 34:1535–1542

    CAS  PubMed  Google Scholar 

  9. Rogers PM, Boxall F, Allott CP, Stephens TC, Kelland LR (2002) Sequence-dependent synergism between the new generation platinum agent ZD0473 and paclitaxel in cisplatin-sensitive and -resistant human ovarian carcinoma cell lines. Eur J Cancer 38:1653–1660

    Article  CAS  PubMed  Google Scholar 

  10. Rowinsky EK, Cazenave LA, Donehower RC (1990) Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 82:1247–1259

    CAS  PubMed  Google Scholar 

  11. Rowinsky EK, Flood WA, Sartorius SE, Bowling KM, Ettinger DS (1997) Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer. Invest New Drugs 15:129–138

    Article  CAS  PubMed  Google Scholar 

  12. Scagliotti GV, Crino L, Pozzi E, Corgna E, Palladino M, Masiero P, Salsano V, Gentile A, Tonato M (1996) Preliminary results of a dose-finding study of paclitaxel and carboplatin in patients with advanced non-small cell lung cancer. Semin Oncol 23 [6 Suppl 16]:80–83

    Google Scholar 

  13. Scagliotti GV, Crino L, Pozzi E, Corgna E, Selvaggi G, Novello S, Salsano G, Gentile A, Palladino M, Marracolo F, Tonato M (1999) Phase I/II dose finding study of paclitaxel and carboplatin in advanced non-small cell lung cancer. Lung Cancer 25:39–46

    Article  CAS  PubMed  Google Scholar 

  14. Schiller J (2001) Current standards of care in small-cell and non-small cell lung cancer. Oncology 61 [Suppl 1]:3–13

    Google Scholar 

  15. Schiller J, Bonomi P, Modiano M, Cornett P, Koehler M (2001) Activity of ZD0473 in small-cell lung cancer: an update in patients relapsing after one prior chemotherapy regimen (abstract 219). Eur J Cancer 37 [Suppl 6]:S62

  16. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) 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 92:205–216

    CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Chris Twelves

    Present address: Tom Connors Cancer Research Centre, Cancer Research Unit, University of Bradford, Bradford, BD7 1DP, UK

  2. Alan Anthoney

    Present address: University of Leeds, Leeds, LS9 7TF, UK

Authors and Affiliations

  1. Cancer Research UK Department of Medical Oncology, Beatson Laboratories, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK

    Chris Twelves, Alan Anthoney & Stan Kaye

  2. Department of Thoracic Oncology, Groβhansdorf Hospital, Groβhansdorf, Germany

    Martin Reck & Ulrich Gatzemeier

Authors
  1. Chris Twelves
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Reck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan Anthoney
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulrich Gatzemeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stan Kaye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chris Twelves.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Twelves, C., Reck, M., Anthoney, A. et al. A phase I study of ZD0473 combined with paclitaxel for the treatment of solid malignancies. Cancer Chemother Pharmacol 52, 277–281 (2003). https://doi.org/10.1007/s00280-003-0633-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-003-0633-9

Keywords

Search

Navigation