A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer

• Published in: Cancer 2012-05, Vol.118 (9), p.2378-2384
• Main Authors: Moulder, Stacy, Gladish, Gregory, Ensor, Joe, Gonzalez‐Angulo, Ana Maria, Cristofanilli, Massimo, Murray, James L., Booser, Daniel, Giordano, Sharon H., Brewster, Abeena, Moore, Julia, Rivera, Edgardo, Hortobagyi, Gabriel N., Tran, Hai T.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Breast Neoplasms - drug therapy; Docetaxel; Drug Administration Schedule; Early Termination of Clinical Trials; Everolimus; Female; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Maximum Tolerated Dose; Medical sciences; metastatic breast cancer; Middle Aged; Neutropenia - chemically induced; phase 1; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Sirolimus - pharmacokinetics; Taxoids - administration & dosage; Taxoids - pharmacokinetics; Tumors
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.26571

BACKGROUND: Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction. METHODS: Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40‐75 mg/m2 intravenously on day 1 of a 21‐day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21‐day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose‐limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts. RESULTS: Fifteen patients were treated. Dose‐limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m2. Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination. CONCLUSIONS: Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs. Cancer 2012. © 2011 American Cancer Society. Although everolimus (RAD001) has been successfully combined with weekly paclitaxel, this study demonstrates that combination therapy with docetaxel is not feasible due to toxicity, predominately myelosuppression. These findings are likely due to drug interactions, as both docetaxel and everolimus, but not paclitaxel, are cleared through CYP3A4.