Background: Several investigational studies including MBC reported that erythropoiesis-stimulating agent (ESA) treatment beyond correction of anemia decreased survival and locoregional tumor control, and/or increased adverse effects, especially thrombotic vascular events (TVEs). These studies were reviewed at 3 FDA Oncologic Drugs Advisory Committee Meetings (2004, 2007, and 2008). Other studies and well-conducted meta-analyses did not suggest adverse effects on tumor outcomes when ESAs are used according to the prescribing information in subjects receiving chemotherapy, however, no study rigorously evaluated tumor outcomes.

This Phase 3 study is the largest MBC trial in subjects receiving EPO for chemotherapy induced anemia specifically designed and conducted to assess progression-free survival (PFS) as the primary endpoint. Conducted as a post-marketing requirement, the study has been regularly and intensively monitored by an Independent Data Monitoring Committee (IDMC) of internationally recognized experts in the fields of MBC treatment, clinical research, and statistics.

Methods: EPO-ANE-3010 (ClinicalTrials.gov #NCT00338286) is a multinational (19 countries and 223 participating sites) study with 2,098 subjects who are anemic and receiving first- or second-line standard chemotherapy for MBC. Key inclusion criteria: histologically confirmed MBC, stage IV disease and at least 1 measurable metastatic lesion according to Response Evaluation Criteria in Solid Tumors (RECIST); hemoglobin (Hb) ≤11 g/dL, Eastern Cooperative Oncology Group performance score 0 or 1. Key exclusion criteria: metastasis to bone only, receiving anticoagulants or endocrine therapy. Subjects were randomly assigned (1:1) to receive either standard supportive care for treatment of anemia (SOC) plus 40,000 IU EPO given subcutaneously weekly up to 4 weeks after the last dose of cytotoxic chemotherapy, or to SOC alone. Randomization was stratified by line of chemotherapy and HER2/NEU status. EPO dose was held for Hb >12 g/dL. Disease was assessed every 8 weeks for the first year, and then every 12 weeks until disease progression (PD) or death. Tumor response was determined according to modified RECIST 1.0 criteria by Investigators and Blinded Central Review. Overall survival (OS) follow up continued after PD.

The primary endpoint is PFS. Secondary endpoints include OS, time to tumor progression, and overall response rate and safety assessments (including incidence and severity of TVEs). For this non-inferiority study, a sample size of 1,650 disease progression or death events was determined to provide over 80% power to rule out a 15% hazard rate increase (i.e., hazard ratio of 1.15, epoetin alfa vs. control) in PFS with a 1-sided Type I error rate 0.025. The study is fully accrued with 2014 projected key dates: clinical cut-off at 1650 PFS events, July; database lock, September; IDMC agreement on presentation of final results, mid-November. Both primary and secondary endpoints will be fully reported.

Citation Format: Brian Leyland-Jones, Igor Bondarenko, Gia Nemsadze, Vitaliy Smirnov, Iryna Litvin, Irakli Kokhreidze, Lia Abshilava, Mikheil Janjalia, Rubi Li, KC Lakshmaiah, Beka Samkharadze, Oksana Tarasova, Ranjan Kumar Mohapatra, Yaroslav Sparyk, Sergey Polenkov, Vladimir Vladimirov, Liang Xiu, Bruce Kimelblatt, Kris Deprince, Ilya Safonov, Els Vercammen, Peter Bowers. A randomized, open-label, multicenter, phase 3 study of epoetin alfa (EPO) plus standard supportive care versus standard supportive care in anemic patients with metastatic breast cancer (MBC) receiving standard chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S5-07.