Matthew A. Spear

Phase 1 First-in-Human Trial of the Vascular Disrupting Agent Plinabulin (NPI-2358) in Patients with Solid Tumors or Lymphomas

Purpose: Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies. Experimental Design: Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m2 to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow. Results: Thirty-eight patients were enrolled. A dose of 30 mg/m2 was selected as the RP2D based on the adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient blood pressure elevations, with DCE-MRI indicating decreases in tumor blood flow (Ktrans) from 13.5 mg/m2 (defining a biologically effective dose) with a 16% to 82% decrease in patients evaluated at 30 mg/m2. Half-life was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L. Conclusions: At the RP2D of 30 mg/m2, plinabulin showed a favorable safety profile, while eliciting biological effects as evidenced by decreases in tumor blood flow, tumor pain, and other mechanistically relevant adverse events. On the basis of these results additional clinical trials were initiated with plinabulin in combination with standard chemotherapy agents. Clin Cancer Res; 16(23); 5892–99. ©2010 AACR.

Vascular Disrupting Agents (VDA) in Oncology: Advancing Towards New Therapeutic Paradigms in the Clinic

Vascular Disrupting Agents (VDA) are a potential new class of oncology drugs that have garnered attention recently as a number of these agents have entered into Phase 2-3 studies. Currently available data suggest how the subsequent evolution of these agents into clinical practice may proceed, with new therapeutic paradigms based on similarities, differences and interactions with current standard of care agents. In particular, the broadly successful group of agents targeting angiogenesis through the Vascular Endothelial Growth Factor (VEGF) pathway, can be contrasted to the VDAs that principally disrupt established tumor vasculature through a different set of molecular targets. Although the angiogenesis inhibitors may benchmark where other vascularly targeted agents such as VDAs may be successful, the differences in terms of efficacy and safety profiles lead to important differentiation in how VDAs are likely to be used. Although the majority of VDAs bind tubulin, significant differences also exist between VDAs and cytotoxic agents, including tubulin targeted agents such as taxanes and vinca alkyloids. Clinical trial data is now available for several VDAs allowing such assessment. Data of yet has been the strongest in NSCLC, with indications of how these drugs may be developed beneficially in subsets of patients such as those with squamous cell histology or at risk of bleeding events. Other indications being aggressively pursued include prostate carcinoma, ovarian carcinoma, sarcomas and astrocytomas. The field also continues to advance with investigation into how to optimally schedule administration of VDAs and what effects might be class effects and/or markers of efficacy.

Abstract C30: Phase 1/2 study of the vascular disrupting agent (VDA) plinabulin (NPI‐2358) combined with docetaxel in patients with non‐small cell lung cancer (NSCLC)

Background: Plinabulin is a vascular disrupting agent (VDA) that binds ‐ tubulin, destabilizing tumor vascular endothelial cytoskeletal architecture and leading to selective collapse of established tumor vasculature. With a structure differing from other ‐tubulin binding VDAs, preclinical studies suggested improvements in toxicology and efficacy leading to clinical assessment of plinabulin. VDAs have been of particular interest given indications of significant activity in NSCLC, as well as potential differentiation from other agents in terms of utility in certain patient subsets such as those with squamous cell carcinoma (SCC) or at risk for bleeding events. Plinabulin was seen to act synergistically with docetaxel in murine models of NSCLC, resulting in the initiation of this clinical trial (the ADVANCE study). Methods: Patients with advanced NSCLC having received prior chemotherapy were enrolled (patients with other malignancies could be enrolled during the Phase 1 portion). Patients were permitted to have been previously treated with bevacizumab, as well as VEGFR or EGFR targeted agents. Docetaxel (75 mg/m2) was given on Day 1 and plinabulin on Days 1 & 8 in 21‐day cycles. During Phase 1, the dose of plinabulin was escalated from the single agent biologic effect dose (BED) of 13.5 mg/m2 to determine a Recommended Phase 2 Dose (RP2D) in combination with docetaxel. During Phase 2, 154 patients are randomized to receive docetaxel with or without plinabulin at the RP2D, with overall survival compared as the primary outcome. Results: 13 patients were enrolled into the Phase 1 portion, of which 10 had NSCLC. The dose of plinabulin was escalated to 30 mg/m2, thus 30 mg/m2 of plinabulin with 75 mg/m2 docetaxel was selected as the RP2D. Toxicites were as expected with either agent alone. Nausea, vomiting, fatigue, fever, tumor pain, and diarrhea were most frequently seen, with one DLT of nausea, vomiting, dehydration and neutropenia observed at 30 mg/m2. Changes in expected pharmacokinetics of the 2 drugs in combination were not seen, and the best response in patients with evaluable NSCLC was higher with the combination than expected with docetaxel alone, with 6/8 having reductions in tumor measurements and 2/8 reaching partial response (>30% reduction). Based on these outcomes the Phase 2 portion of the study was initiated. Enrollment is half complete, with 77 patients having been enrolled. Patients with all histologies of NSCLC, including SCC are being enrolled. Interim data from these patients will be analyzed in October 2009 and presented. Conclusions: In this Phase 1/2 evaluation of plinabulin in combination with docetaxel, during the Phase 1 portion PK and safety data did not demonstrate an unexpected toxicities or an adverse drug‐drug interaction, and activity was encouraging relative to the 5–10% response rate reported with docetaxel alone in this population. Efficacy and safety are now being compared in the Phase 2 portion with a 1:1 randomization into 2 arms [docetaxel (75 mg/m2) +/− plinabulin (30 mg/m2)]. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C30.

Abstract A107: Clinical trial combining proteasome (NPI‐0052) and HDAC (vorinostat) inhibition in melanoma, pancreatic, and lung cancer

Background: Combining proteasome inhibition with HDAC inhibition has recently been shown to provide synergistic anti‐tumor activity in preclinical and clinical studies. A proposed mechanism centers around inhibition of both of the major protein disposal mechanisms of the cell, resulting in near complete lack of ability of the tumor to dispose of normal pro‐apoptotic and growth inhibitory peptides. The bi‐cyclic structure of NPI‐0052 is not polypeptide based as are other proteasome inhibitors, leading to rapid, broad and prolonged inhibition of all 3 proteolytic sites, with unique proteasome inhibition, toxicology and efficacy profiles. Preclinical studies indicated marked synergy with a number of HDAC inhibitors in solid tumor and hematologic malignancy models. Materials and Methods: Patients with melanoma, pancreatic carcinoma and NSCLC having failed standard therapies were given NPI‐0052 intravenously on a weekly (Days 1, 8 and 15) schedule dose escalation, in combination with vorinostat 300 mg orally on the first 16 days of each 28 day cycle. A 3+3 design was used with the dose of NPI‐0052 escalated from 0.15 mg/m2 to 0.7 mg/m2. In addition to standard safety laboratory studies, proteasome inhibition and pharmacokinetics are also assayed in blood on Day 1 and multiple subsequent time points. Results: 20 patients have been enrolled into this study. There has not been an indication of increased toxicity with the combination, and the dose of NPI‐0052 has been escalated to and is currently being administered at the full single agent dose without dose limiting toxicity. Pharmacokinetic data indicate a short half life of NPI‐0052 ( Conclusions: The combination of full dose NPI‐0052 with vorinostat is tolerable and has not resulted in unexpected safety findings (of note the toxicity profile is dissimilar to that reported with other proteasome inhibitors, in not inducing neutropenia, thrombocytopenia or peripheral neuropathy). Pharmacokinetic and pharmacodynamic results were likewise consistent with what are expected from prior data with each drug. Enrollment continues to further characterize the combination at the recommended phase 2 dose. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A107.

Abstract C33: A two‐arm phase 1 clinical trial with NPI‐0052, a novel proteasome inhibitor

Background: The bi‐cyclic structure of NPI‐0052 differentiates it from other proteasome inhibitors which are structurally polypeptide based, leading to its differential properties of rapid, broad and prolonged inhibition of all 3 proteolytic sites, and unique proteasome inhibition, toxicology and efficacy profiles. Preclinical studies indicated an increased therapeutic ratio with activity in hematologic and solid tumor malignancies leading to the initiation of Phase 1 clinical trials. These biologic differences also led to the question of whether twice weekly administration schedule, as is typical for other proteasome inhibitors, or more convenient once weekly schedule would be preferable. Materials and Methods: Patients with solid tumor, lymphoma, leukemia or myeloma diagnoses failing after standard therapies were given NPI‐0052 intravenously on a weekly or twice weekly arm in the dose escalation portion of this study. Subsequently 10 patient Recommended Phase 2 dose Cohorts of patients with lymphomas, CLL and myeloma are enrolled. Proteasome inhibition and pharmacokinetics are also assayed in whole blood, and/or peripheral blood mononuclear cells (PBMC) on Day 1 and multiple subsequent time points. Results: 44 patients have been enrolled into this study. Notable adverse events have been fatigue, parosmia/dysgeusia, transient peri‐infusion site pain, lymphopenia, headaches, dizziness / unsteady gait, closed‐eye visuals, cognitive changes. Peripheral neuropathy, neutropenia and thrombocytopenia do not appear to be induced. Pharmacokinetic data indicate a short T1/2 and large Vss. Proteasome inhibition assays demonstrated inhibition of chymotrypsin‐like activity of up to 88% Day 1 and 100% Day 15. Inhibition accumulates initially in whole blood presumably secondary to the inability of RBC to synthesize new proteasomes, whereas inhibition recovers over several days in PBMC further leading the question as to an optimal dosing regimen. Stable disease, regression or response, have been reported in mantle cell lymphoma, myeloma, Hodgkin9s lymphoma, cutaneous marginal zone lymphoma, follicular lymphoma, sarcoma, prostate carcinoma and melanoma. Conclusions: NPI‐0052 produces expected or greater levels of proteasome inhibition in patient blood samples, with a toxicity profile that is dissimilar to what is reported with other proteasome inhibitors. The profile of the proteasome inhibition, toxicity and efficacy profiles that have been revealed during this clinical trial and correlative studies reveals further basis and hypothesis as to what an optimal dosing regimen might be, which is being assessed in this study. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C33.