A Phase II, Randomized, Multi-Centre, Open-Label, Active-Controlled, Dose-Finding Trial of F-627 (benefilgrastim) in Women with Breast Cancer Receiving Myelotoxic Chemotherapy

Neutropenia is common in patients receiving myelotoxic chemotherapy. Benefilgrastim, an rhG-CSF dimer (rhG-CSF-FC fusion protein), is a once-per-cycle therapy for prophylactic neutrophil support. In this Phase II trial, 230 women with stage I-IV breast cancer are to be treated for 4 chemotherapy cycles with either docetaxel/cyclophosphamide (TC) or doxorubicin/docetaxel/cyclophosphamide (TAC) chemotherapy, with each cycle lasting approximately 21 days. Patients will be randomized to receive either benefilgrastim or pegfilgrastim (Neulasta; 6 mg fixed dose) one day after chemotherapy during each cycle, as a subcutaneous injection. Dose levels of benefilgrastim examined are 80 µg/kg (TC patients only), and 240 and 320 µg/kg (TC and TAC patients). The primary endpoint is the duration of grade 3/4 neutropenia in chemotherapy cycle 1. As of August 1, 2014, 232 patients have completed chemotherapy cycle 1; safety and efficacy were analyzed for these enrolled patients.

For the TC chemotherapy regimen, a total of 141 patients were randomized (ratio = 1:1:1:1) into 4 arms (80, 240, and 320 µg/kg benefilgrastim or 6 mg pegfilgrastim). In the TAC chemotherapy regimen, a total of 91 patients were randomized (ratio = 1:1:1) into 3 arms (240 and 320 µg/kg benefilgrastim or 6 mg pegfilgrastim). The incidence of grade 3/4 and grade 4 neutropenia and their mean durations in cycle 1 are provided in Table 1. There were higher incidences of grade 3/4 and grade 4 neutropenia in the TAC regimen compared to the TC regimen.

The safety profiles of benefilgrastim and pegfilgrastim were similar. A total of 10 SAEs were reported in 6 patients with the majority (7 SAEs in 4 patients) occurring in those receiving pegfilgrastim. The most commonly observed treatment emergent adverse events (>10% of total TC + TAC patients) were: alopecia, nausea, asthenia, neutropenia, bone pain, and fatigue. The rates were similar amongst treatment regimens and treatment groups.

In summary, a single subcutaneous injection of benefilgrastim 240 or 320 µg/kg provided neutrophil support to patients treated with both the TC and TAC chemotherapy regimens. The safety profile of benefilgrastim was comparable to that of pegfilgrastim during multiple chemotherapy cycles. The results suggest a potential use of benefilgrastim for the management of severe neutropenia in cancer patients undergoing high dose chemotherapy.