Open-Label, Phase 1 Study to Evaluate Duration of Severe Neutropenia after Same-Day Dosing of Eflapegrastim in Patients with Breast Cancer Receiving Docetaxel and Cyclophosphamide (NCT04187898)

Background: Eflapegrastim (Rolontis®, Efla) is a long-acting granulocyte-colony stimulating factor (G-CSF), consisting of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Efla is not a biosimilar and represents the first myeloid growth factor innovation in more than 15 years. In preclinical studies with chemotherapy-induced neutropenic rats, Efla showed ~3-fold higher exposure in serum and higher exposure in bone marrow at similar doses compared to pegfilgrastim (Peg). The duration of neutropenia (DN) was shown to be significantly shorter with Efla vs Peg when administered on the same day or 24-hours post-chemotherapy. Additionally, the DN after Efla administered on the same day as chemotherapy was similar to the DN 24 hours post-chemotherapy. Moreover, in two Phase 3 studies that randomized a total of 643 patients with early-stage breast cancer (ESBC) to either Efla (3.6 mg G-CSF n=314) or Peg (6 mg G-CSF n=329) given ~ 24 hours after docetaxel and cyclophosphamide (TC), the duration of severe neutropenia (DSN) was statistically noninferior in patients treated with Efla compared to Peg. As a standard of practice, G-CSF products require administration 24 hours after chemotherapy. Since Efla preclinical and clinical results suggest that the increased activity of Efla may provide effective prophylaxis against chemotherapy-induced neutropenia when administered on the same day as chemotherapy, the purpose of this study is to assess the feasibility of giving Efla same-day (at 3 different dosing timepoints) in patients receiving TC for the treatment of ESBC.

Study Design and Methods: This is a randomized, schedule finding, multicenter, Phase 1, open-label study evaluating the same-day administration of 13.2 mg/0.6 mL Efla following IV infusion of docetaxel (75 mg/m²) and cyclophosphamide (600 mg/m²) in patients with ESBC.

Treatment: On Cycle 1, Day 1, patients will be randomized 1:1:1 to Efla dose administration schedules of 0.5, 3, and 5 hours after TC. In Cycles 2-4, Efla will be administered ~ 24 hours following the administration of TC for all treatment arms.

Clinical Endpoints: The primary endpoint is DSN (ANC <0.5×10⁹/L) in Cycle 1. The secondary endpoints for Cycle 1 administration include the incidence of SN, time to recovery from SN, incidence of Grade 3 febrile neutropenia, incidence of neutropenic complications, and pharmacokinetics (PK) of Efla. Blood for hematology will be drawn daily for the first 10 days and then on Day 1 of Cycles 2-4.

Inclusion Criteria: This study is enrolling histologically confirmed (operable stage I-IIIA) patients with ESBC, who are >18 years of age, are candidates for neoadjuvant or adjuvant TC, have an ECOG of <2, with adequate hematological, renal, and hepatic function.

Exclusion Criteria: Patients will be excluded if they have an active or concurrent malignancy, or locally recurrent/metastatic or bilateral breast cancer, a life-threatening disease, a known sensitivity or previous reaction to E. coli derived products, exposure to a G-CSF agent within 3 months, history of bone marrow or hematopoietic stem cell transplant, radiotherapy or surgery within 30 days, are pregnant or are breast-feeding.

Statistical Methods: A sample size of 15 patients per dosing schedule arm was determined to provide adequate precision for the 95% CI of the DSN and secondary endpoints, including PK parameters, assuming a standard deviation of 1.0 days based on the prior studies. A safety evaluation will be performed once the first three patients in each arm have completed Cycle 1.

Target Accrual: 45 patients (15 subjects/arm). Enrollment began in April 2020.