Protective-2 (BPI-2358-106): A Confirmatory Trial to Demonstrate Superiority of the Plinabulin+Pegfilgrastim (Plin/Peg) Combination Versus Standard of Care Pegfilgrastim for the Prevention of Chemotherapy-Induced Neutropenia (CIN) in Breast Cancer (BC) Patients (pts)
Authors: Blayney Douglas W. , Mohanlal Ramon , Huang Lan 
Published: November 2020

Introduction.
BC is a potentially curable cancer condition, with more favorable outcomes with avoidance of CIN. Peg is the standard of care for the prevention of CIN, but does not fully prevent CIN (Masuda 2015). Plin is a novel, small molecule, non-G-CSF agent, given as a single dose per cycle, by 30 min IV infusion, 30 min after Chemotherapy (Chemo), on the same day of Chemo. In contrast to Peg, Plin does not cause bone pain or thrombocytopenia (Blayney JAMA Onc in press). The mechanism of action (MoA) of Plin exerts its CIN preventive effects predominantly in week 1 of the cycle, whereas Peg primarily in week 2. This was the rationale to combine these two agents, to obtain superior CIN protection throughout the entire cycle (Blayney ASCO 2019). Data from Phase (Ph) 2 portion of PROTECTIVE-2 (NCT0329457) with the Plin/Peg combination demonstrated superiority in CIN protection vs Peg alone, with a favorable safety/tolerability profile (Blayney, St Gallen 2019). Additionally, the addition of Plin to Peg almost eradicated the Peg-induced bone pain. The Ph 3 portion of PROTECTIVE-2 aims to confirm superiority of the Plin/Peg combination vs Peg standard of care for avoidance of CIN and Bone Pain-prevention.
Trial Design
PROTECTIVE-2 is a global, multicenter, randomized, double-blind Study to Evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Arm 2) in preventing Severe Neutropenia (defined as Absolute Neutrophil Count (ANC) of &lt;0.5×10E9/L) in early stage (Stage I and II) and Stage III BC (node positive or node negative with a high risk of recurrence) pts with ECOG status 0 or 1 (target of approximately n=222 pts) receiving myelosuppressive Chemo with Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC). A non-binding Interim Analysis was a planned at approximately n=100 pts completing Cycle 1. TAC and Plin were given on Day (D) 1 and Peg on D2.
ANC (Covance Central Laboratory) was assessed before and after during Cycle 1 on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Bone Pain was assessed by a validated at regular timepoints in Cycle 1 with a validated PRO questionnaire.
The Primary objective was to compare the percentage of pts with a Duration of Severe Neutropenia (DSN) of 0 days in treatment Cycle 1 between the Plin/Peg vs Peg alone.
Secondary objectives in Cycle 1 included mean DSN, mean ANC NADIR, average change in Bone Pain from baseline, the rate of composite risk (infection, FN, hospitalization, significant disability, life threatening and death), and over 4 Cycles, the percentage of patients with Relative Dose Intensity (RDI) &lt; 85%.
Following the pre-planned Interim Analysis, the DSMB recommended the trial to continue without modifications. Current Status: Patient accrual has been completed.

Disclosures
Blayney: BeyondSpring Pharma: Other: Research Funding to Institution. Mohanlal:BeyondSpring Pharma: Current Employment, Current equity holder in publicly-traded company. Huang:BeyondSpring Pharma: Current Employment, Current equity holder in publicly-traded company.