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An Open-Label Phase 2 Study of Twice-Weekly Bortezomib and Intermittent Pegylated Liposomal Doxorubicin in Patients With Ovarian Cancer Failing Platinum-Containing Regimens
  1. Gabriella Parma, MD*,
  2. Rosanna Mancari, MD*,
  3. Gianluca Del Conte, MD,
  4. Giovanni Scambia, MD,
  5. Angiolo Gadducci, MD§,
  6. Dagmar Hess, MD,
  7. Dionyssios Katsaros, MD,
  8. Cristiana Sessa, MD#,
  9. Andrea Rinaldi, PhD#,
  10. Francesco Bertoni, MD#,
  11. Andrea Vitali, ScD**,
  12. Carlo Vittorio Catapano, MD, PhD#,
  13. Silvia Marsoni, MD**,
  14. Helgi van de Velde, MD, PhD†† and
  15. Nicoletta Colombo, MD*,‡‡
  1. *Division of Gynaecology, Istituto Europeo di Oncologia (IEO), Milan, Italy;
  2. Unit of New Drugs and Innovative Therapies, Istituto Nazionale dei Tumori, Milan, Italy;
  3. Division of Gynecologic Oncology, Università Cattolica Sacro Cuore, Campobasso, Italy;
  4. §Department of Procreational Medicine, Università di Pisa, Pisa, Italy;
  5. Department of Internal Medicine, Kantonsspital, St Gallen, Switzerland;
  6. Gynecologic Oncology Unit, Ospedale Sant’Anna, Turin, Italy;
  7. #Istituto Oncologico della Svizzera Italiana (IOSI), Ospedale San Giovanni, Bellinzona, Switzerland;
  8. **Southern Europe New Drug Organization (SENDO), Milan, Italy;
  9. ††Janssen Research and Development, Division of Janssen Pharmaceutica, N.V., Beerse, Belgium; and
  10. ‡‡University of Milan Bicocca, Milan, Italy.
  1. Address correspondence and reprint requests to Nicoletta Colombo, MD, Istituto Europeo di Oncologia (IEO), Milan, Italy, Via Ripamonti, 435-20141 Milano. E-mail: nicoletta.colombo@ieo.it.

Abstract

Background Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD.

Methods Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m2 intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m2 intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study.

Results Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinum-sensitive group, 9 responses were observed (median duration, 4.8 months). The platinum-resistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease.

Conclusions The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.

  • Bortezomib
  • Pegylated liposomal doxorubicin
  • Ovarian cancer
  • Proteasome inhibitor

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Footnotes

  • Funding: This work was supported by Janssen Pharmaceutical NV, Belgium. The sponsor also provided a formal review of this manuscript.

  • Previous presentations: The results of this study have been presented as a poster at 2008 ASCO Annual Meeting, Chicago, Illinois, United States, and is published as an abstract (J Clin Oncol 26: 2008 [May 20 suppl; abstr 5581]).

  • Author contributions: All authors met ICMJE criteria, and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, made the final decision about where to publish these data, and approved submission to the journal. Andrea Vitali was an employee of Southern Europe New Drug Organization (SENDO), Milan, Italy at the time of study conduction and analysis and left the company. Specifically, GP, RM, GDC, GS, AG, DH, DK, and CS were participating study investigators and contributed to data collection and interpretation. NC, SM, and HvdV contributed to study design, data interpretation, and literature analysis. AV and HvdV oversaw the statistical analyses and provided interpretation of the data. AR, FB, and CVC designed, performed, and supervised pharmacogenomic studies. CVC contributed to data interpretation and manuscript preparation.

  • Disclosure: HvdV holds stock in, and is an employee of, Janssen Research and Development, Beerse, Belgium. Janssen is the manufacturer of bortezomib and pegylated liposomal doxorubicin. All remaining authors have declared no conflicts of interest.

  • Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).

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