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TPS128 Background: Plinabulin (Plin) is a microtubule-destabilizing agent (MDA) that inhibits the polymerization of tubulin monomers and leads to disruption of the tumor vasculature. It has been shown in clinical studies of advanced NSCLC to produce a significantly longer duration of response when combined with docetaxel versus docetaxel alone (NCT00630110). MDAs were also shown to trigger the maturation of dendritic cells and the production of pro-inflammatory cytokines, thereby enhancing T-cell proliferation. Pre-clinical studies have shown that MDAs in combination with immune checkpoint inhibitors (ICI) demonstrated a superior response rate and survival when compared to ICI alone. Nivolumab is an anti-PD-1 antibody that is FDA approved for previously treated metastatic NSCLC regardless of PD-L1 expression. We hypothesized that the combination of Plin and Nivolumab will enhance the immune response, resulting in a higher response rate and longer overall survival. Methods: This is an open label single center phase I trial. The Dose Escalation Portion (Part 1) employs a 3+3 design with dose escalation of Plin starting at 13.5mg/m2 (biologically effective dose as single agent), combined with the FDA approved dose of Nivolumab 240mg. Plin is given on days 1,8, and 15 of 28- day cycles and Nivolumab is given on days 1 and 15. The dose of Plin will be escalated to 20mg/m2, 30 mg/m2, and 40mg/m2 until the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is determined. The Expansion Cohort (Part 2) will enroll 20 patients with NSCLC to be treated at the RP2D, including the patients who will have received this dose in Part 1. Treatment will continue until disease progression, development of unacceptable toxicity, or a protocol-defined reason for discontinuation. Eligible patients include metastatic NSCLC who have failed platinum-based doublet and regardless of prior anti-PD-1/PD-L1 antibody treatment. Part 1 is enrolling in an expanded cohort 2 due to one dose-limiting toxicity (DLT) in this group. Clinical trial information: NCT02812667.

126 Background: Plinabulin (Plin) is a small molecule with tumor-inhibiting and immune-enhancing effects by targeting Dendritic Cells (DCs). In preclinical studies, Plin induces DC maturation and the production of MHCII, CD40, CD80 and CD86 and related antigen-specific T-cell activation. Plin had synergistic anticancer efficacy with PD1+CTLA4inhibitors in animal models. In addition, Plin increases expression of IL-1β, IL-6, IL-12 in DC cell, which cytokines protect neutrophils against apoptosis. In a Phase 2 (Ph2) trial, the addition of Plin to Docetaxel (Plin+Doc; n = 38) in NSCLC patients (pts) with a measurable lesion, improved mOS with 4.6 mo vs Doc alone (n = 38). DOR (a marker of immune effect) was ~1 yr longer (P < 0.05) with Plin+Doc vs Doc alone. Plin exerted immune-enhancing effects (DOR), without increasing Immune-Related AEs (IR-AEs). This may suggest that Plin exerts immune-enhancing and anti-inflammatory effects. Methods: Prospective, randomized Ph2 clinical trial (NCT00630110) and non-clinical studies. Results: In-vitro screens showed that Plin is a PDE4-inhibitor, and clinical evidence (p < 0.03; n = 90) of PDE4-inhibition with Plin was observed in Ph2. PDE4-inhibitors have steroid-like effects and are approved for the treatment of Inflammatory disorders, and thus have the potential to prevent IR-AEs. In addition, Plin prevented chemo-induced Neutropenia (CIN), through a mechanism, different from G-CSF, in non-clinical (with various chemotherapies) and Ph2. In Ph2, Gr 4 Neutropenia occurred in 5% with Plin+Doc vs 33 % off pts with Doc (p < 0.0003) in Cycle 1, day 8. Plin is given 30 min after chemo (on the same day of chemo), and does not cause bone pain. G-CSF is given 24 hr after chemo, and causes bone pain in most pts. Conclusions: Plin exerts anticancer immune-enhancing effects, combined with anti-inflammatory effects, due to PDE4-inhibition. Plin holds the promise of an agent with anti-cancer efficacy, while also mitigating IR-AEs and CIN. Therefore, Plin is an attractive candidate for combination therapy with PD1-inhibitors (or PD-L1 inhibitors), PD1+CTLA-inhibitor, or PD1-inhibitor/chemotherapy.

139 Background: Plinabulin (Plin) is a small molecule with tumor-inhibiting and immune-enhancing effects. In preclinical studies, Plin induces dendritic cell maturation and related IL-1β, IL-6 and IL-12 release, enhances antigen-specific CD4 T-cell proliferation, reduces regulatory T-cells and M2 macrophages in tumor tissue. Plin had synergistic efficacy with checkpoint inhibitors (PD-1 +/- CTLA-4) in animal models of tumor growth. Plin is targeting critical steps in the immune-cascade, independent from that of PD-1/PD-L1 binding. Methods: In a Phase 2 clinical trial, patients (pts) with and without measurable lung lesion were randomized to docetaxel (D) alone at 75 mg/m2 or Plin with D (Plin+D), in 30 mg/m2 or 20 mg/m2 Plin cohorts, given every 3 weeks (NCT00630110). The primary efficacy endpoint was mOS. Secondary endpoints were safety assessments, DOR, PFS, ORR. PD-L1 tumor status was not characterized. Results: In the 30 mg/m2 cohort, n=50 patients received 30 mg/m2 Plin+ D and n=55 patients received D alone; 72% had measurable lung lesion. In pts with a measurable lung tumor, Plin+D (n=38) was numerically more effective vs. D alone (n=38). mOS, PFS and ORR were 11.3 mo, 3.7 mo, and 18% respectively for Plin+ Doc, and 6.7 mo, 2.9 mo, and 10.5% resp for D alone. DOR (a marker of immune effect) with the Plin+D vs. D alone was 12.7 mo vs. 1 mo (p2 Plin cohort was more effective than the 20 mg/m2 cohort as an anticancer agent. Conclusions: Plin added to D increases efficacy vs. D alone most likely through an immune-related mechanism independent from PD1/PD-L1 intervention and mitigates the known D-related safety concerns, without increasing IR-AEs. The Plin+D combination might represent an effective and cost-effective alternative to Nivolumab, in particular in PD-L1 negative NSCLC. A global phase 3 trial with Plin+D vs. D alone is underway in pts with at least one measurable NSCLC lesion. Clinical trial information: NCT00630110.