Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC
- Conditions
- Non-Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT02504489
- Lead Sponsor
- BeyondSpring Pharmaceuticals Inc.
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 559
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Docetaxel (D) Docetaxel (D) A treatment cycle is 21 days. Treatment will be repeated until disease progression is detected by imaging studies or unacceptable toxicities are encountered. On Day 1, all patients will receive docetaxel 75 mg/m2 by intravenous (IV) infusion over 1 hour. Oral dexamethasone (16 mg, given as 8 mg twice daily) will be given on the day prior to, the day of (Day 1), and the day following docetaxel infusion (Day 2). Antiemetic prophylaxis will be administered according to institutional guideline for docetaxel. Institutional guideline/practice should be followed in the event of infusion/hypersensitivity reaction. Diphenhydramine and dexamethasone infusion may be administered in the event of infusion reaction. Docetaxel + Plinabulin (DP) Docetaxel + Plinabulin (DP) The treatment regimen for Docetaxel (D) will be followed for this arm. In addition, on Days 1 and 8 of the 21 day cycle, patients will receive Plinabulin (P) administered via IV infusion over 60 minutes. On Day 1, the infusion begins 2 hours from the starting time of docetaxel infusion, i.e, approximately 60 minutes from the end of docetaxel infusion. On Day 8, patients must be given an anti-emetic prophylactically before the plinabulin infusion. If emesis persists after Day 8, with a grade \>1, plinabulin will be reduced to 20 mg/m2. Patients from the DP Arm who stop treatment with docetaxel due to toxicity or another medically acceptable reason, may continue treatment with plinabulin alone as previously described. Docetaxel + Plinabulin (DP) Docetaxel (D) The treatment regimen for Docetaxel (D) will be followed for this arm. In addition, on Days 1 and 8 of the 21 day cycle, patients will receive Plinabulin (P) administered via IV infusion over 60 minutes. On Day 1, the infusion begins 2 hours from the starting time of docetaxel infusion, i.e, approximately 60 minutes from the end of docetaxel infusion. On Day 8, patients must be given an anti-emetic prophylactically before the plinabulin infusion. If emesis persists after Day 8, with a grade \>1, plinabulin will be reduced to 20 mg/m2. Patients from the DP Arm who stop treatment with docetaxel due to toxicity or another medically acceptable reason, may continue treatment with plinabulin alone as previously described.
- Primary Outcome Measures
Name Time Method Overall Survival Mid-February 2021 (Approximately 2 years after study initiation) Overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy
- Secondary Outcome Measures
Name Time Method PFS Approximately 2 years after study initiation. Progress-free survival
Severe Neutropenia Day 8 of Cycle 1 Percent of patients without severe neutropenia on Day 8 of Cycle 1
Quality of Life (EORTC QLQ-C30) Approximately 2 years after study initiation. Average Quality of Life score over all observed weeks (scale 0 - 30, higher value represents better outcome)
Q-TWiST Approximately 2 years after study initiation. To compare the mean difference in quality-adjusted time without symptoms of disease and toxicity
QoL (QLQ-LC13) Approximately 2 years after study initiation. To compare the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 global health status/QoL and the combined symptom scales/items (excluding financial difficulties)
Proportion of patients who received docetaxel During 1st 21-day cycle To compare proportion of patients who received docetaxel \>8 cycles, \>10 cycles, and \>12 cycles
Month 18 OS Rate 18 month after study initiation To compare 18-month overall survival rate
Month 36 OS Rate 36 month after study initiation To compare 36-month overall survival rate
Month 24 OS Rate 24-month after study initiation To compare 24-month overall survival rate
ORR Approximately 2 years after study initiation. Overall response rate
DoR Approximately 2 years after study initiation. Duration of response
RDI First 4, 6, 8, 10, and 12 cycles To compare relative dose intensity \[where dose intensity is defined as dose in mg/m2/week\] of docetaxel
Month 12 OS Rate 12 month after study initiation To compare 12-month overall survival rate
Trial Locations
- Locations (57)
Pacific Cancer Medical Center, Inc.
🇺🇸Anaheim, California, United States
Peachtree Hematoloy-Oncology Consultants, PC
🇺🇸Atlanta, Georgia, United States
The Fourth Hospital of Hebei Medical University
🇨🇳Shijiazhuang, Hebei, China
Jiangyin People's Hospital
🇨🇳Jiangyin, Jiangsu, China
Jilin Province Cancer Hospital
🇨🇳Changchun, Jilin, China
West China Hospital of Sichuan University
🇨🇳Chendu, Sichuan, China
Tianjin People's Hospital
🇨🇳Tianjin, Tianjin, China
Sir Run Run Shaw Hospital, Zhejiang University
🇨🇳Hangzhou, Zhejiang, China
Zhejiang Cancer Hospital
🇨🇳Hangzhou, Zhejiang, China
The First Affiliated Hospital, Zhejiang University
🇨🇳Hanzhou, Zhejiang, China
Shanghai Chest Hospital, Shanghai Jiaotong Univers
🇨🇳Shanghai, Shanghai, China
The Fifth People's Hospital of Shanghai
🇨🇳Shanghai, Shanghai, China
The First Affiliated Hospital of Xi'an Jiaotong U
🇨🇳Xi'an, Shaanxi, China
Yantai Yuhuangding Hospital
🇨🇳Yantai, Shangdong, China
Liaoning Cancer Hospital & Institute
🇨🇳Shenyang, Liaoning, China
527-Linyi Cancer Hospital
🇨🇳Linyi, Shangdong, China
Shandong Cancer Hospital
🇨🇳Jinan, Shangdong, China
Perth Oncology/Mount Hospital
🇦🇺Perth, Western Australia, Australia
St John of God Hospital, Subiaco
🇦🇺Subiaco, Western Australia, Australia
Fiona Stanley Hospital
🇦🇺Murdoch, Western Australia, Australia
Kansas University Medical Center
🇺🇸Westwood, Kansas, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Ironwood Cancer & Research Centers
🇺🇸Chandler, Arizona, United States
Memorial Health Care System
🇺🇸Colorado Springs, Colorado, United States
Cancer Center of Central Connecticut
🇺🇸Plainville, Connecticut, United States
University of Louisville-Brown Cancer Center
🇺🇸Louisville, Kentucky, United States
Hattiesburg Clinic Hematology/Oncology
🇺🇸Hattiesburg, Mississippi, United States
Central Care Cancer Center
🇺🇸Bolivar, Missouri, United States
Michigan Center of Medical Research
🇺🇸Farmington Hills, Michigan, United States
Allegheny Health Network
🇺🇸Pittsburgh, Pennsylvania, United States
Toledo Cancer Center
🇺🇸Toledo, Ohio, United States
Cookeville Regional Medical Center Cancer Center
🇺🇸Cookeville, Tennessee, United States
Peninsula and South East Oncology
🇦🇺Melbourne, Victoria, Australia
Gosford Hospital
🇦🇺Gosford, New South Wales, Australia
Adult Mater Hospital
🇦🇺South Brisbane, Queensland, Australia
Epworth Hospital
🇦🇺Richmond, Victoria, Australia
Anhui Provincial Hospital
🇨🇳Hefei, Anhui, China
Cancer Hospital Chinese Academy of Medical Science
🇨🇳Beijing, Beijing, China
Beijing Cancer Hospital
🇨🇳Beijing, Beijing, China
The First Affiliated Hospital of Xiamen University
🇨🇳Xiamen, Fujian, China
The PLA General Hospital
🇨🇳Beijing, Beijing, China
Zhongshan Hospital Xiamen University
🇨🇳Xiamen, Fujian, China
Guizhou Provincial Hospital
🇨🇳Guiyang, Guizhou, China
Affiliated Cancer Hospital of Harbin Medical Unive
🇨🇳Ha'erbin, Heilongjiang, China
The Second Xiangya Hospital of Central South Unive
🇨🇳Changsha, Hunan, China
Henan Cancer Hospital
🇨🇳Zhengzhou, Henan, China
Jiangsu Cancer Hospital
🇨🇳Nanjing, Jiangsu, China
Nantong Tumor Hospital
🇨🇳Nantong, Jiangsu, China
Jiangxi Provincial Tumor Hospital
🇨🇳Nanchang, Jiangxi, China
Affiliated Tumor Hospital of Xinjiang Medical Univ
🇨🇳Ürümqi, Xinjiang, China
Wake Forest Baptist Health
🇺🇸Winston-Salem, North Carolina, United States
Innovative Clinical Research Institute
🇺🇸Whittier, California, United States
Orchard Healthcare Research Inc.
🇺🇸Skokie, Illinois, United States
Blacktown Cancer Centre
🇦🇺Blacktown, New South Wales, Australia
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
Border Medical Oncology Research Unit
🇦🇺East Albury, New South Wales, Australia
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States