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Phase I Clinical Trial of the Mammalian Target of Rapamycin Inhibitor Everolimus in Combination With Oral Topotecan for Recurrent and Advanced Endometrial Cancer
  1. Carlos Acevedo-Gadea, MD*,
  2. Alessandro D. Santin, MD, PhD,
  3. Susan A. Higgins, MD,
  4. Shweta Urva, PhD§,
  5. Elena Ratner, MD,
  6. Dan-Arin Silasi, MD,
  7. Masoud Azodi, MD,
  8. Thomas Rutherford, MD, PhD,
  9. Peter E. Schwartz, MD and
  10. Maysa M. Abu-Khalaf, MBBS*
  1. * Sections of Medical Oncology, and
  2. Gynecologic Oncology, and
  3. Department of Therapeutic Radiology, School of Medicine, Yale University, Yale Comprehensive Cancer Center, New Haven, CT; and
  4. §Novartis Pharmaceuticals Corp, East Hanover, NJ.
  1. Address correspondence and reprint requests Maysa M. Abu-Khalaf, MBBS, Section of Medical Oncology, Yale University School of Medicine, Yale Comprehensive Cancer Center, 300 George Street, Suite 120, New Haven, CT 06511. E-mail: maysa.abu-khalaf{at}


Objectives Preclinical data suggest that mammalian target of rapamycin inhibitors may potentiate the efficacy of topotecan. We evaluated the optimal schedule of oral topotecan in combination with everolimus in patients with endometrial cancer.

Methods Women with a history of advanced or recurrent endometrial cancer were enrolled. Escalating dose of oral topotecan (1.5 mg/m2, 1.9 mg/m2, and 2.3 mg/m2) daily on days 1 to 5 and everolimus (5 mg every other day, 5 mg daily, and 10 mg daily) were administered in a 21-day cycle. A “run-in” treatment of topotecan daily for 5 days followed by everolimus for 7 days (4–7 doses depending on dose level) was administered for the purpose of pharmacokinetic assessments.

Results Ten patients were enrolled on the study, and 9 were evaluable for safety analysis. A total of 28 cycles were administered (range, 1–10 cycles per patient). The patients had a median age of 73 years (range, 42–79 years). Previous lines of chemotherapy were 1 (n = 2), 2 (n = 5), 3 (n = 2), and 4 (n = 1). Seven patients had previous vaginal brachytherapy, and 2 had pelvic external beam radiation therapy. The median number of cycles (including cycle 1) is 2 (range, 1–10). Dose-limiting toxicity occurred in 3 patients (1 patient treated with 1.9-mg/m2 topotecan and 5-mg everolimus given every other day as well as 2 patients treated with 1.9-mg/m2 topotecan and 5-mg of everolimus daily) and included neutropenia and thrombocytopenia. Seven patients were evaluable for response. Stable disease was the best response in 3 patients who completed the 3, 4, and 10 cycles each.

Conclusions The dose-limiting toxicity for the combination of oral topotecan and everolimus was myelosuppression. The maximum tolerated dose was topotecan 1.9 mg/m2 on days 1 to 5 in combination with oral everolimus 5 mg every other day. Administration of higher dose of each agent in combination was limited because of overlapping myelosuppression.

  • Endometrial cancer
  • mTOR
  • Everolimus
  • Topotecan

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  • Novartis Pharmaceuticals provided financial support to conduct this clinical trial and provided the study drug everolimus. Glaxo SmithKline provided the study drug topotecan.

  • M.M.A.-K. had a consultancy/advisory board with Novartis. S.U. is employed and has stock option with Novartis. D.-A.S. is a consultant with Olympus and is a speaker for Genzyme.