Skip to main content
SpringerLink
Log in

A phase I-II study of elacytarabine (CP-4055) in the treatment of patients with ovarian cancer resistant or refractory to platinum therapy

  • Clinical Trial Report
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Treatment of patients with recurrent ovarian cancer remains a challenge, and there is a need for new and more effective agents. A phase I-II study was designed to determine the recommended dose (RD) and the anti-tumour effect of a prolonged administration of elacytarabine, the elaidic ester of cytarabine, in patients with refractory/resistant recurrent ovarian cancer.

Experimental design

The primary objective of the dose escalation phase I part was to determine the RD for elacytarabine when given twice for five consecutive days in a 4-week schedule, D1-5 and D8(+2)-12(+2) q4w. Three to six patients were to be enrolled at each dose level. The start dose was elacytarabine 75 mg/m2/day. The phase II part was designed as a two-step study based on response.

Results

A total of 28 patients entered the study, 17 patients in the phase I part and 11# patients in phase II. Three dose levels were tested: 75 mg/m2/day in 3 patients, 100 mg/m2/day in 7 + 11# patients, and 125 mg/m2/day in 7 patients. Three (17.6%) patients in phase I experienced a dose limiting toxicity (DLT), all at the 125 mg/m2/day dose level, establishing the lower dose of 100 mg/m2/day as the RD. The DLTs were neutropenia grade 4 according to the Common Terminology Criteria for Adverse Events (CTCAE) and thrombocytopenia grade 4 (2 patients), and vomiting grade 2 with hospitalisation and hypokalaemia grade 3 (1 patient). The best response was a clinically meaningful stabilization observed in 3 patients. In two of them, the disease stabilization exceeded the previous platinum-free interval (PFI).

Conclusions

The RD for elacytarabine was 100 mg/m2/day, D1-5 and D8-12 q4w. The safety profile was comparable to the safety profiles reported in previous clinical studies with elacytarabine in solid tumours. Despite some longer-lasting disease stabilisations, two of them exceeding the previous progression-free interval, further investigations of elacytarabine in the ovarian cancer indication are not warranted.

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

Fig. 1

References

  1. Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT et al (2006) Carcinoma of the ovary. FIGO 6th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 95(Suppl 1):S161–S192

    Article  PubMed  Google Scholar 

  2. Rubin SC, Randall TC, Armstrong KA, Chi DS, Hoskins WJ (1999) Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings. Obstet Gynecol 93:21–24

    Article  PubMed  CAS  Google Scholar 

  3. Pignata S, Cannella L, Leopardo D, Pisano C, Bruni GS, Facchini G (2011) Chemotherapy in epithelial ovarian cancer. Cancer Lett 303:73–83

    Article  PubMed  CAS  Google Scholar 

  4. Gordon AN, Fleagle JT, Guthrie D et al (2001) Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312–3322

    PubMed  CAS  Google Scholar 

  5. Gordon AN, Tonda M, Sun S et al (2004) Long term survival advantage for women treated with pegylated liposomal doxorubicin versus topotecan in a phase III randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 95:1–8

    Article  PubMed  CAS  Google Scholar 

  6. Meier W, du Bois A, Reuss A, Kuhn W, Olbricht S, Gropp M, Richter B, Lück HJ, Kimmig R, Pfisterer J (2009) Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie ovarian cancer study group (AGO-OVAR). Gynecol Oncol 114:199–205

    Google Scholar 

  7. Pectasides D, Psyrri A, Pectasides M et al (2006) Optimal therapy for platinum resistant recurrent ovarian cancer: doxorubicin, gemcitabine or topotecan? Expert Opin Pharmacother 7:975–987

    Article  PubMed  CAS  Google Scholar 

  8. Ferrandina G, Paris I, Ludovisi M et al (2005) Gemcitabine and liposomal doxorubicin in the salvage treatment of ovarian cancer: updated results and long-term survival. Gynecol Oncol 98:267–273

    Article  PubMed  CAS  Google Scholar 

  9. Rose PG, Maxson JH, Fusco N et al (2001) Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages. Gynecol Oncol 82:323–328

    Article  PubMed  CAS  Google Scholar 

  10. Ferrandina G, Ludovisi M, Lorusso D et al (2008) Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 26:890–896

    Article  PubMed  CAS  Google Scholar 

  11. Armstrong D (2002) Relapsed ovarian cancer: challenges and management strategies for a chronic disease. Oncologist 7(Suppl 5):20–28

    Google Scholar 

  12. Bolwell BJ, Cassileth PA, Gale RP (1988) High dose cytarabine: a review. Leukaemia 2:253–260

    CAS  Google Scholar 

  13. Plunkett W, Gandhi V (1993) Cellular pharmacodynamics of anticancer drugs. Semin Oncol 20:50–63

    PubMed  CAS  Google Scholar 

  14. Rustum YM, Raymakers RA (1992) 1-Beta-arabinofuranosylcytosine in therapy of leukaemia: preclinical and clinical overview. Pharmacol Ther 56:307–321

    Google Scholar 

  15. Grant S (1998) Ara-C: cellular and molecular pharmacology. Adv Cancer Res 72:197–233

    Article  PubMed  CAS  Google Scholar 

  16. Gailani S, Nussbaum A (1976) Correlation of response to 1-beta- D-arabinofuranosyl cytosine and metabolism of drug by tumour. J Med 7:93–102

    PubMed  CAS  Google Scholar 

  17. Bajetta E, Verusio C, Bonfante V, Bonadonna G (1986) Cytarabine and cisplatin in advanced malignant melanoma. Cancer Treat Rep 70:1441–1442

    Google Scholar 

  18. Chabner BA (1993) Anticancer drugs. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer: principles and practice of oncology, 4th edn. JB Lippincott Co, Philadelphia, pp 365–369

    Google Scholar 

  19. Someya H, Waud WR, Parker WB (2006) Long intracellular retention of 4′-thio-arabinofuranosylcytosine 5′-triphosphate as a critical factor for the antisolid tumour activity of 4′-thioarabinofuranosylcytosine. Cancer Chemother Pharmacol 57:772–780

    Article  PubMed  CAS  Google Scholar 

  20. Breistøl K, Balzarini J, Sandvold ML, Myhren F, Martinsen M, De Clercq F et al. (1999) Antitumour activity of P-4055 (Elaidic Acid-Cytarabine) compared to cytarabine in metastatic and s.c. human tumour xenograft models. Cancer Res 59:2944–2949

    Google Scholar 

  21. Ross DD, Chen SR, Cuddy DP (1990) Effects of 1-beta-Darabinofuranosylcytosine on DNA replication intermediates monitored by PH-step alkaline elution. Cancer Res 50:2658–2666

    PubMed  CAS  Google Scholar 

  22. Bergman AM, Kuiper CM, Voorn DA, Comijn EM, Myhren F, Sandvold ML et al (2004) Antiproliferative activity and mechanism of action of fatty acid derivatives of arabinofuranosylcytosine in leukaemia and solid tumour cell lines. Biochem Pharmacol 67:503–511

    Article  PubMed  CAS  Google Scholar 

  23. Bergman AM, Kuiper CM, Myhren F, Sandvold ML, Hendriks HR, Peters GJ (2004) Antiproliferative activity and mechanism of action of fatty acid derivatives of arabinosylcytosine (ara-C) in leukaemia and solid tumour cell lines. Nucleosides Nucleotides Nucleic Acids 23:1523–1526

    Article  PubMed  CAS  Google Scholar 

  24. Dueland S, Aamdal S, Lind MJ, Thomas H, Sandvold ML, Gaullier JM, Rasch W (2009) Intravenous administration of CP-4055 (ELACYT) in patients with solid tumours. A phase I study. Acta Oncol 48(1):137–145

    Google Scholar 

  25. Delaunoit T, Raymond E, Awada A, Savinelli F, Culine S, Rasch W et al. (2006) A three schedule phase I trial of CP-4055, weekly and q2 weeks in patients with advanced or metastatic solid tumours. J Clin Oncol (Suppl):267 (abstract)

  26. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The co-authors Kjell Hernes and Wenche Rasch are employees at the company Clavis Pharma ASA. F. Amant is Sr. Clinical Investigator for the Research Fund-Flanders (FWO). The other co-authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Istituto Nazionale Tumori, IRCCS “Fondazione G. Pascale”, Naples, EU, Italy

    S. Pignata, C. Pisano & L. Cannella

  2. Leuven Cancer Institute, Gynaecological Oncology, Leuven, Belgium

    F. Amant, K. Leunen & I. Vergote

  3. Università Cattolica del Sacro Cuore, Rome, Italy

    G. Scambia & D. Lorusso

  4. Centro di Riferimento Oncologico, Aviano, Italy

    R. Sorio

  5. Ospedale Fatebenefratelli, Rome, Italy

    E. Breda

  6. Clavis Pharma, Oslo, Norway

    W. Rasch & K. Hernes

  7. Division of Medical Oncology, Department of Urology and Gynecology, National Cancer Institute of Naples, Via Mariano Semmola, 80131, Naples, Italy

    S. Pignata

Authors
  1. S. Pignata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Amant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Scambia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Sorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. Breda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W. Rasch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K. Hernes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Pisano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K. Leunen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D. Lorusso
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L. Cannella
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. I. Vergote
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Pignata.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pignata, S., Amant, F., Scambia, G. et al. A phase I-II study of elacytarabine (CP-4055) in the treatment of patients with ovarian cancer resistant or refractory to platinum therapy. Cancer Chemother Pharmacol 68, 1347–1353 (2011). https://doi.org/10.1007/s00280-011-1735-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-011-1735-4

Keywords

Search

Navigation