Abstract OT3-1-02: A Phase 3 randomized, double-blind trial comparing PF-05280014 + docetaxel and carboplatin vs. trastuzumab + docetaxel and carboplatin for neoadjuvant treatment of operable HER2+ breast cancer
Authors: Jacobs Ira , Coiro Jennifer , Hilton Fiona , Orazem John , Abbas Richat , Zacharchuk Charles 
Published: May 2015

Abstract
Background: PF-05280014 is being developed as a potential biosimilar to trastuzumab. PF-05280014 demonstrated similarity to trastuzumab in nonclinical evaluations. In a Phase I trial in healthy subjects, pharmacokinetic (PK) characteristics and safety profile of PF-05280014 were similar to those of trastuzumab. The goal of this Phase 3 trial is to demonstrate that the efficacy and safety of PF-05280014 + docetaxel and carboplatin are similar to those of trastuzumab sourced from the EU (trastuzumab-EU) + docetaxel and carboplatin in the neoadjuvant treatment of women with HER2-positive operable breast cancer.
Trial design: In this randomized, double-blind trial, subjects will be randomized (1:1) with stratification by primary tumor size (&lt;5 cm or ≥5 cm), estrogen receptor (ER) status, and progesterone receptor (PR) status to PF-05280014 + docetaxel and carboplatin or trastuzumab-EU + docetaxel and carboplatin. PF-05280014 or trastuzumab (8 mg/kg in Cycle 1; 6 mg/kg thereafter over 90 min) will be administered followed by docetaxel (75 mg/m2) and carboplatin (target area under the curve [AUC]: 6 mg/mL/min; 30- to 60-minute infusion) every 3 weeks for 6 treatment cycles. The primary objective is to compare the percentages of patients with Cycle 5 Ctrough (trastuzumab serum trough concentration) &gt;20 μg/mL in the neoadjuvant setting. Secondary objectives include measures of tumor control, safety, immunogenicity, PK, and to explore the relationship between drug exposure and pathologic complete response (pCR).
Eligibility criteria: Female subjects with known ER and PR status ≥18 years with confirmed HER2 overexpressing breast cancer and a plan for definitive surgical resection and neoadjuvant chemotherapy, Eastern Cooperative Oncology Group status 0 or 1, normal left ventricular ejection fraction and normal laboratory values are eligible. Key exclusion criteria are bilateral or inflammatory breast cancer; prior treatment, including chemotherapy, endocrine therapy, biologic therapy, radiation or surgery (except diagnostic biopsy); other concomitant active malignancy or history of malignancy in the past 5 years or presence of known distant metastases. All subjects must provide informed consent.
Specific aims: The goal of this Phase 3 trial is to demonstrate that PF-05280014 in combination with docetaxel and carboplatin has similarity in PK (trough level) and comparable efficacy and safety versus trastuzumab-EU + docetaxel and carboplatin in subjects with operable HER2-positive breast cancer in the neoadjuvant setting.
Statistical methods: This study tests whether percentage of subjects with steady state (Cycle 5) Ctrough &gt;20 μg/mL of PF-05280014 is similar to that of trastuzumab-EU, using a noninferiority margin of -12.5% tested with α=0.025 (one-sided). Assuming the percentages of subjects reaching steady state is 95% with trastuzumab-EU and 93% with PF-05280014, 188 subjects (94/arm) will be needed to achieve 85% power.
Target accrual: 220 subjects.
Citation Format: Ira Jacobs, Jennifer Coiro, Fiona Hilton, John Orazem, Richat Abbas, Charles Zacharchuk. A Phase 3 randomized, double-blind trial comparing PF-05280014 + docetaxel and carboplatin vs. trastuzumab + docetaxel and carboplatin for neoadjuvant treatment of operable HER2+ breast cancer [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 OT3-1-02.