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Pegylated Liposomal Doxorubicin and Gemcitabine in a Fixed Dose Rate Infusion for the Treatment of Patients With Poor Prognosis of Recurrent Ovarian Cancer: A Phase Ib Study
  1. Guillermo Crespo, PhD*,
  2. Marta Sierra, PhD,,
  3. Raquel Losa, PhD,,
  4. José Pablo Berros, MD*,
  5. Noemí Villanueva, MD*,,
  6. Joaquín Fra, MD*,,
  7. Paula J. Fonseca, PhD*,,
  8. María Luque, MD*,,
  9. Yolanda Fernández, MD*,,
  10. Pilar Blay, PhD*,,
  11. Miguel Sanmamed, MD*,
  12. Carolina Muriel, PhD*,
  13. Emilio Esteban, PhD*, and
  14. Ángel J. Lacave, PhD*,
  1. *Department of Medical Oncology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain;
  2. Laboratory of Medical Oncology, HUCA, Oviedo, Spain;
  3. Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Obra Social CajAstur, Oviedo, Spain.
  1. Address correspondence and reprint requests to Guillermo Crespo, PhD, Hospital Universitario Central de Asturias, C/ Celestino Villamil s/n, Oviedo 33005, Spain. E-mail: gcrespoherrero{at}


Introduction Pegylated liposomal doxorubicin (PLD) is currently the reference treatment for platinum-resistant ovarian cancer. The combination of PLD and gemcitabine and the administration of gemcitabine at a fixed dose rate infusion (FDRI) seem to have additive activity in this disease setting. We have launched a phase Ib study with the combination of FDRI gemcitabine followed by PLD in recurrent ovarian cancer with a platinum-free interval of less than 1 year, with parallel pharmacokinetic and pharmacogenetic studies.

Methods The starting dose of gemcitabine was 1500 mg/m2, 10 mg/m2 per minute, every 2 weeks (±250 mg gemcitabine titration depending on toxicity), followed by PLD 35 mg/m2 every 4 weeks. Gemcitabine pharmacokinetics and equilibrative nucleoside transporter 1, deoxycytidine kinase, and ribonucleotide reductase M1 gene expression levels were studied.

Results Thirty-five patients were treated at 3 different dose levels (DL). Dose level 1 was not tolerated. Nonfrail patients continued to be treated at DL-1 (G 1250 mg/m2 on day 1 and PLD 35 mg/m2 on days 1 and 15). Of 10 evaluable nonfrail patients, 4 displayed dose-limiting toxicity. Frail patients were treated at DL-2 (G 1250 mg/m2 on day 1 and PLD 35 mg/m2 on days 1 and 15). Of the 12 evaluable frail patients, 3 developed dose-limiting toxicity. Neutropenia, palmar-plantar erythrodysesthesia and stomatitis were the most common toxicities. The response rate was 42.8% (95% confidence interval [CI], 34.5%-51.1%), with 17.1% (6/35) complete responses and 25.7% (9/35) partial responses. The median progression-free survival was 7.7 months (95% CI, 2.2-13.1). The median overall survival was 13.9 months (95% CI, 9.4-18.4). The administration of PLD after gemcitabine did not influence gemcitabine pharmacokinetics or its metabolites. The addition of PLD to gemcitabine caused a larger and longer induction of the ribonucleotide reductase M1 gene. Patients with higher baseline levels of deoxycytidine kinase had longer progression-free survival.

Conclusion The recommended dose for a phase II study of patients with recurrent ovarian cancer having poor prognosis is PLD, 35 mg/m2 on day 1, and gemcitabine, 1000 mg/m2 on days 1 and 15 delivered at an FDRI of 10 mg/m2 per minute in 28-day cycles.

  • Ovarian carcinoma
  • Gemcitabine
  • Pegylated liposomal doxorubicin
  • Platinum-resistant OC
  • Fixed dose rate infusion
  • Phase I

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