Douglas W Blayney1, Qingyuan Zhang2, Jifeng Feng3, Yanqiu Zhao4, Igor Bondarenko5, Ihor Vynnychenko6, Nadezhda Kovalenko7, Santosh Nair8, Emad Ibrahim9, Dmitriy Petrovich Udovista10, Ramon Mohanlal11, Stephan Ogenstad12, Ene Ette13, Lihua Du14, Lan Huang11, Yuan-Kai Shi15,16. 1. Stanford Cancer Institute, Stanford, California. 2. Harbin Medical University Cancer Hospital, Harbin, China. 3. Department of Medical Oncology, Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China. 4. Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. 5. Dnipropetrovsk Medical Academy, Ukraine. Dnepropetrovsk, Ukraine. 6. Sumy Regional Clinical Oncology Dispensary, Sumy State University, Sumy, Ukraine. 7. Volgograd Regional Clinical Oncology Dispensary, Volgograd, Russia. 8. Mid Florida Hematology and Oncology Center, Orange City. 9. Redlands Community Hospital, Redlands, California. 10. SBI of Healthcare Oncology Dispensary No. 2, Ministry of Health of Krasnodar Region, Sochi, Russia. 11. BeyondSpring Pharmaceuticals, New York, New York. 12. Statogen Consulting, Wake Forest, North Carolina. 13. Anoixis Corporation, Natick, Massachusetts. 14. Wanchun Bulin Pharmaceuticals Limited, Dalian, China. 15. Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 16. Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
Abstract
IMPORTANCE: Plinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects. OBJECTIVE: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non-small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020. INTERVENTIONS: All patients received docetaxel 75 mg/m2 on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m2) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles. MAIN OUTCOMES AND MEASURES: The primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1. RESULTS: Of the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m2 (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected. CONCLUSIONS AND RELEVANCE: Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m2, will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03102606.
IMPORTANCE: Plinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects. OBJECTIVE: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non-small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020. INTERVENTIONS: All patients received docetaxel 75 mg/m2 on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m2) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles. MAIN OUTCOMES AND MEASURES: The primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1. RESULTS: Of the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m2 (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected. CONCLUSIONS AND RELEVANCE: Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m2, will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03102606.
Authors: Daniëlle Copmans; Sara Kildgaard; Emma Roux; Michèle Partoens; Gert Steurs; Xinhui Wang; Wim M De Borggraeve; Camila V Esguerra; Alexander D Crawford; Thomas O Larsen; Peter A M de Witte Journal: Pharmaceuticals (Basel) Date: 2022-02-18