Clinical Evidence of Granulocyte-Monocyte Progenitor (GMP) Stem Cell Involvement in Plinabulin's Mechanism of Action (MoA) for the Prevention of Docetaxel (Doc) Chemotherapy (Chemo)-Induced Neutropenia (CIN)

Introduction:

Plinabulin (Plin) is being developed as a novel non-Granulocyte colony stimulating factor (G-CSF) for CIN prevention. Previously we reported that Plin was equally effective as Pegfilgrastim for the prevention of grade 4 CIN in a Phase (Ph) 2 trial in NSCLC patients (Pts) receiving 75 mg/m2 Doc (Blayney, ASH 2017, 2018). Plin is single dose per cycle, on the same day of (and 30 min after) Chemo, does not cause bone pain and has anticancer activity. Plin is separately developed as an anti-cancer agent in a global Ph3 trial in NSCLC pts (NCT02504489). Preclinical studies showed that Plin reversed Chemo-induced inhibition of progenitor LSK differentiation in bone marrow (Ghosh, AACR 2018). We have shown that peripheral blood CD34+ hematopoietic stem cell counts increase in chemo plus plin treated patients (Blayney ASH, 2018). Since normal differentiation of GMPs leads to increases in peripheral blood myelo-monocytic (M) and granulocytic cells [neutrophils(N), eosinophils (E) and basophils (B)], we hypothesize that if GMPs are involved in Plin's CIN MoA, increases in N count would positively correlate with increases in M, E and B counts.

Method: The Ph 3 portion of study BPI-2358-105 (NCT03102606) evaluated Plin (40mg) head-to-head with Pegfilgrastim (6mg) for the prevention of Doc-induced CIN in patients (pts) with NSCLC, BC or HRPC. Blood N,M,B and E counts were taken at screening, pre-and post-dose during Cycle 1 and analyzed by a central laboratory (Covance). Pts received dexamethasone (Dex) pre-medication on day (D) 0,1,2, and on D1 Docetaxel (Doc) 75 mg/m2 followed by Plin (40 mg), 30 min after completion of Doc. Here we only include data from a pre-planned interim analysis, and from the Plin arm only (n=52), and we calculated the maximum increase in N,M,E and B on day (D) 5,6,7,8,9,10 15 as % of screening counts, since N,M,E and B counts on D1-D5 are confounded by demargination and Dex effects on these counts.

Results: Pearson correlation coefficients (r) with associated p-values were calculated for maximum increases in N and compared with those for M,E and B, and summarized below.

Conclusions: Correlation of M, E, and B with neutrophil count increase, further confirms our proposed MoA for Plin prevention of CIN: Plin protects the neutrophil precursor from chemotherapy induced damage in bone marrow. We will further explore this MoA in other CIN studies.

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