Originally published as JCO Early Release 10.1200/JCO.2008.21.3033 on August 17 2009

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Randomized Phase II Study Comparing Two Schedules of Everolimus in Patients With Recurrent/Metastatic Breast Cancer: NCIC Clinical Trials Group IND.163

From the BC Cancer Agency–Southern Interior, Kelowna, British Columbia, Canada.

Corresponding author: Susan L. Ellard, MD, BC Cancer Agency–Southern Interior, 399 Royal Ave, Kelowna, British Columbia, Canada, V1Y 5L3; e-mail: sellard{at}bccancer.bc.ca.

Purpose To evaluate the safety and efficacy of oral everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in two different schedules in minimally pretreated patients with metastatic breast cancer and to explore for possible biologic correlates of response.

Patients and Methods Patients who received no or one prior chemotherapy regimen for metastatic breast cancer were entered onto this multicenter, noncomparative, randomized phase II study of everolimus 10 mg daily versus 70 mg weekly; the multinomial end points of response and progression were evaluated at 8 weeks. A two-stage accrual design was used, with 15 evaluable patients in each schedule in stage 1. Only daily therapy met criteria for continuing, and another 15 patients were added. pAKT, PTEN, carbonic anhydrase 9, estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were evaluated for possible correlation with response.

Results The most common drug-related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough, and pneumonitis. Pneumonitis occurred at higher than expected rates and seemed to be schedule dependent, with the highest incidence on the daily schedule. Response rate with daily therapy was 12% (95% CI, 3.4% to 28.2%) compared with 0% (95% CI, 0.0% to 20.6%) for weekly therapy. Twenty-seven percent of patients on daily therapy discontinued treatment compared with 13% on weekly therapy (16% v 6% with pneumonitis, respectively). No biologic correlates of response could be identified, although there were trends favoring benefit in ER-positive and HER2-negative metastatic breast cancer.

Conclusion Oral everolimus has activity in metastatic breast cancer that is schedule dependent. Daily therapy with 10 mg is worthy of further study in this patient population.

Supported by the Canadian Cancer Society, Novartis Pharmaceuticals, and grants from the Canadian Institute of Health Research (M.O.) and AstraZeneca (M.O.).

Presented in part at the 18th Annual Symposium of the European Organisation for Research and Treatment of Cancer–American Association for Cancer Research–National Cancer Institute, November 7-10, 2006, Prague, Czech Republic, and at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00255788 [ClinicalTrials.gov] .

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