Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC

Non-Small Cell Lung Cancer

To compare the overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. Secondary purposes of the study are: * To compare overall response rate (ORR) of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. * To compare progression free survival (PFS) of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. * To compare incidence of Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 × 109/L) on Day 8 (+/- 1 day) of Cycle 1 of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. * To compare 24-month and 36-month OS rate of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease.

Lung cancer is the leading cause of cancer-related mortality worldwide. According to the World Health Organization's Global Cancer Observatory, there were an estimated 2.09 million new cases and 1.76 million deaths worldwide in 2018 (GLOBOCAN, 2018, Fact Sheet N⁰39). The lung cancer incidence and mortality in China is relatively high compared to most countries with an estimated 774,323 new cases and 690,567 deaths in 2018 (GLOBOCAN, 2018, Fact Sheet N⁰160 China). In the US, as per the estimates of the National Cancer Institute, there would be about 228,820 new cases and 135,720 deaths from lung cancer in 2020 accounting for approximately 22.4% of all cancer deaths (SEER program, 2020). About 84% of lung cancers are NSCLCs in the US (American Cancer Society, 2020). The prognosis for patients with advanced or metastatic NSCLC, either at initial diagnosis or recurrence, remains grim. The standard of care has been chemotherapy with agents including platinum analogs, taxanes, vinca alkaloids, and pemetrexed with vascular endothelial growth factor inhibitors and for patients with appropriate disease genotypes, epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors. First-line Therapy: For patients without specific molecular target, first-line therapy is usually a programmed cell death protein 1 (PD-1)-inhibitor or a platinum-containing, double agent regimen. Platinum can be either cisplatin or carboplatin, and the most commonly used drugs combined with platinum include paclitaxel, docetaxel, gemcitabine, and vinorelbine; other drugs such as irinotecan, etoposide, and vinblastine. The arrival of immunotherapy with the PD-1 inhibitor pembrolizumab effectively changed the first-line standard. Pembrolizumab is very effective, with a long Duration of Response (DoR), however response rates remain suboptimal (approximately 45% in first line \[Keytruda® Prescribing Information. 2020\]). Most patients will eventually fail first line therapy and docetaxel remains a valid treatment option when NSCLC patients fail to respond to targeted or immune-based therapies or become refractory to such therapies. For patients intolerant to platinum-containing regimens, platinum-free double-agent chemotherapy regimens are used as an alternative. For patients with an Eastern Cooperative Oncology Group score of 2 and elderly patients, single-agent or double agent regimens are recommended. Approval has been obtained in China for the single agent gefitinib to be used in first-line treatment of locally advanced or metastatic NSCLC patients with sensitive mutation of EGFR tyrosine kinase gene. Second-line Therapy: Drugs used for second-line treatment include docetaxel, pemetrexed, EGFR-tyrosine kinase inhibitor (TKI) for EGFR mutant patients, and the checkpoint inhibitors (such as nivolumab and pembrolizumab). Several second-line treatment drugs and regimens (docetaxel, pemetrexed, and ramucirumab combined with docetaxel) have been approved as single agents or combination for second-line therapy for locally advanced or metastatic NSCLC with EGFR wild type with limited efficacy, characterized by limited clinical improvement or overall survival (OS). EGFR wild type represents around 85% of western NSCLC population, and around 70% of Asian NSCLC population. Checkpoint inhibition with PD 1/programmed death-ligand 1 (PD-L1) inhibitors in combination with chemotherapy or other checkpoint inhibitors have moved into first line and are increasingly not an option for 2nd/3rd line. This has created a situation where docetaxel-based regimens have become standard-of-care in 2nd/3rd line NSCLC. Therefore, the evaluation of plinabulin combined with docetaxel versus docetaxel alone has become highly relevant. Docetaxel, a taxane, binds to and stabilizes tubulin, thereby inhibiting microtubule disassembly resulting in cell cycle arrest at the G2/M phase and subsequent cell death. In patients with NSCLC, previously treated with a platinum-based chemotherapy, second-line therapy with docetaxel afforded a median OS in the range from 5.7 to 7.5 months (Fossella, 2000; Shepherd, 2000). The most common AEs included infections, neutropenia, anemia, febrile neutropenia (FN), hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia (Taxotere Prescribing Information, 2020). Since the approval of docetaxel in 1999 as the second-line treatment for advanced or metastatic NSCLC, other drugs, namely pemetrexed and erlotinib, have been approved for the same indication. However, despite the availability of newer treatments, patient survival has not improved over that achieved with docetaxel. The OS in these studies was found to remain in the range of 5.6 to 8.3 months (Hanna et al., 2004; Kim et al., 2008; Shepherd et al., 2005). A retrospective analysis of the plinabulin Phase 2 study suggests that plinabulin prolongs survival in NSCLC patients with measurable lung tumors. The expectation is that patients with a measurable lung lesion may still harbor antigens that are immunogenic, thus capable of still stimulating the immune system. Docetaxel treatment is expected to release these immunogens and plinabulin is expected to enhance presentation of these immunogens via dendritic cell activation, to the T-cell repertoire. This plinabulin study investigates the efficacy and safety of plinabulin and docetaxel combination in patients with EGFR wild type NSCLC and progressing tumors requiring second- or third- line therapy for advanced or metastatic disease after failing a platinum-containing regimen. The primary endpoint is OS, with docetaxel monotherapy as an active comparator.

Australia, China, United States