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

Non-Small Cell Lung Cancer Clinical Trial

— DUBLIN-3  

Official title:

Randomized Blinded Phase III Assessment of Second or Third-Line Chemotherapy With Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced Non-Small Cell Lung Cancer and With at Least One Measurable Lung Lesion

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02504489
• Other study ID #: BPI-2358-103
• Status: Completed
• Phase: Phase 3
• Start date: December 2015
• Est. completion date: May 23, 2021

Study information

• Verified date: September 2022
• Source: BeyondSpring Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 559
• Est. completion date: May 23, 2021
• Est. primary completion date: March 23, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

INCLUSION CRITERIA:

1. Males and females = 18 years of age

2. ECOG performance status = 2.

3. Histopathologically or cytologically confirmed non-squamous or squamous NSCLC.

4. Disease progression during or after treatment with one or two treatment regimen(s) Treatment regimens can be chemotherapy, targeted therapy, biological therapy, or immunotherapy for advanced (Stage IIIB) or metastatic disease (Stage IV). Modification of a regimen to manage toxicity with a different drug does not constitute a new regimen. Maintenance therapy following platinum-based chemotherapy is not considered as a separate regimen. Adjuvant or neoadjuvant chemotherapy and/or chemo-radiation for early stage disease do not count as prior systemic therapy. Prior radiation therapy is not exclusionary. Prior immunotherapy with a PD-1/PD-L1 inhibitor is not exclusionary. Prior treatment for advanced or metastatic disease must have included a platinum-based regimen. (Treatment of early stage disease [Stage IIIA or earlier] with a platinum-containing therapy does not count).

5. Patients with active brain metastasis or leptomeningeal involvement with brain metastases who are asymptomatic, and whose lesions by imaging are at least stable and without interim development of new lesions for at least 4 weeks may be enrolled. Patients who require continued therapy with steroid medication for management for their brain metastases are eligible; dosing must be stable for at least 4 weeks prior to randomization;

6. Patients must have at least one measurable lung lesion of =10 mm by CT or MRI per RECIST 1.1 criteria. Radiographic tumor assessment is to be performed within 28 days prior to randomization;

7. All patients with non-squamous NSCLC must have been tested for 19 deletion and exon 21 L858R substitution mutation. Only patients without EGFR sensitizing mutations are eligible, and they must have progressed on platinum-based chemotherapy. Patients with known ALK-rearrangements should be treated with an appropriate tyrosine kinase inhibitor (TKI) before entering the study. The TKI regimen would count as a line of treatment.

8. All adverse events of any prior systemic therapy, surgery, or radiotherapy, must have resolved to CTCAE (v4.03) Grade =2, except for neurological adverse events that must have resolved to Grade =1;

9. The following laboratory results from the central laboratory within 14 days prior to Cycle 1 Day 1 study drug administration.

• Hemoglobin =9 g/dL independent of transfusion or growth factor support;
• Absolute neutrophil count =1.5 x 109/L independent of growth factor support;
• Platelet count =100 x 109/L independent of transfusion or growth factor support;
• Serum total bilirubin = ULN, unless the patient has a diagnosis of Gilbert's disease in which case serum bilirubin =3.0 times ULN;
• AST and ALT =2.5 x ULN (=1.5 x ULN if alkaline phosphatase is >2.5 x ULN);
• Serum creatinine =1.5 x ULN;

10. Life expectancy more than 12 weeks;

11. Female patients of childbearing potential have a negative pregnancy test at baseline. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression.

1. Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug.

2. Sexually active women of childbearing potential enrolled in the study must agree to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; (b) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) a vasectomized partner.

3. For male patients who are sexually active and who are partners of premenopausal women: agreement to use two forms of contraception as in criterion 11b above during the treatment period and for at least 3 months after the last dose of study drug.

12. Signed informed consent.

EXCLUSION CRITERIA: Patients with any of the following:

1. Administration of chemotherapy, immunotherapy, biological, targeted, or radiation therapy or investigational agent (therapeutic or diagnostic) within 3 weeks prior to receipt of study medication. Major surgery, other than diagnostic surgery, within 4 weeks before first study drug administration.

2. Significant cardiac history:

• History of myocardial infarction or ischemic heart disease within 1 year (within a window of 18 days) before first study drug administration;
• Uncontrolled arrhythmia;
• History of congenital QT prolongation;
• ECG findings consistent with active ischemic heart disease;
• New York Heart Association Class III or IV cardiac disease;
• Uncontrolled hypertension: blood pressure consistently greater than 150 mm Hg systolic and 100 mm Hg diastolic in spite of antihypertensive medication.

3. Patients who have received prior treatment with docetaxel.

4. Prior transient ischemic attack or cerebrovascular accident within the past year (within an 18-day window). Any neurologic toxicities = Grade 2 within 3 weeks of randomization.

5. History of hemorrhagic diarrhea, inflammatory bowel disease or active uncontrolled peptic ulcer disease. (Concomitant therapy with ranitidine or its equivalent and/or omeprazole or its equivalent is acceptable). History of ileus or other significant gastrointestinal disorder known to predispose to ileus or chronic bowel hypomotility.

6. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.

7. Known infection with human immunodeficiency virus (HIV) or active hepatitis A, B, or C.

8. Known prior hypersensitivity reaction to any product containing polysorbate 80, polyoxyethylene 15 hydroxystearate/Macrogol 15 hydroxystearate (Solutol HS 15/ Kolliphor HS 15).

9. Female subject who is pregnant or lactating.

10. Second malignancy unless in remission for >5 years. (Non-melanoma skin cancer or carcinoma in situ of the cervix treated with curative intent is not exclusionary).

11. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient. Examples of such conditions include uncontrolled diabetes, infection requiring parenteral anti-infective treatment, liver failure, any altered mental status or any psychiatric condition that would interfere with the understanding of the informed consent form.

12. Unwilling or unable to comply with procedures required in this protocol.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• Docetaxel + Plinabulin (DP)
Docetaxel 75 mg/m2 IV + Plinabulin 30 mg/m2
• Docetaxel (D)
Docetaxel 75 mg/m2 IV

Locations

Country	Name	City	State
Australia	Blacktown Cancer Centre	Blacktown	New South Wales
Australia	Border Medical Oncology Research Unit	East Albury	New South Wales
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Peninsula and South East Oncology	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Perth Oncology/Mount Hospital	Perth	Western Australia
Australia	Epworth Hospital	Richmond	Victoria
Australia	Adult Mater Hospital	South Brisbane	Queensland
Australia	St John of God Hospital, Subiaco	Subiaco	Western Australia
China	Beijing Cancer Hospital	Beijing	Beijing
China	Cancer Hospital Chinese Academy of Medical Science	Beijing	Beijing
China	The PLA General Hospital	Beijing	Beijing
China	Jilin Province Cancer Hospital	Changchun	Jilin
China	The Second Xiangya Hospital of Central South Unive	Changsha	Hunan
China	West China Hospital of Sichuan University	Chendu	Sichuan
China	Guizhou Provincial Hospital	Guiyang	Guizhou
China	Affiliated Cancer Hospital of Harbin Medical Unive	Ha'erbin	Heilongjiang
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	Anhui Provincial Hospital	Hefei	Anhui
China	Jiangyin People's Hospital	Jiangyin	Jiangsu
China	Shandong Cancer Hospital	Jinan	Shangdong
China	527-Linyi Cancer Hospital	Linyi	Shangdong
China	Jiangxi Provincial Tumor Hospital	Nanchang	Jiangxi
China	Jiangsu Cancer Hospital	Nanjing	Jiangsu
China	Nantong Tumor Hospital	Nantong	Jiangsu
China	Shanghai Chest Hospital, Shanghai Jiaotong Univers	Shanghai	Shanghai
China	The Fifth People's Hospital of Shanghai	Shanghai	Shanghai
China	Liaoning Cancer Hospital & Institute	Shenyang	Liaoning
China	The Fourth Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	Tianjin People's Hospital	Tianjin	Tianjin
China	Affiliated Tumor Hospital of Xinjiang Medical Univ	Ürümqi	Xinjiang
China	The First Affiliated Hospital of Xi'an Jiaotong U	Xi'an	Shaanxi
China	The First Affiliated Hospital of Xiamen University	Xiamen	Fujian
China	Zhongshan Hospital Xiamen University	Xiamen	Fujian
China	Yantai Yuhuangding Hospital	Yantai	Shangdong
China	Henan Cancer Hospital	Zhengzhou	Henan
United States	Pacific Cancer Medical Center, Inc.	Anaheim	California
United States	Peachtree Hematoloy-Oncology Consultants, PC	Atlanta	Georgia
United States	Central Care Cancer Center	Bolivar	Missouri
United States	Ironwood Cancer & Research Centers	Chandler	Arizona
United States	University of Cincinnati	Cincinnati	Ohio
United States	Memorial Health Care System	Colorado Springs	Colorado
United States	Cookeville Regional Medical Center Cancer Center	Cookeville	Tennessee
United States	Henry Ford Hospital	Detroit	Michigan
United States	Michigan Center of Medical Research	Farmington Hills	Michigan
United States	Hattiesburg Clinic Hematology/Oncology	Hattiesburg	Mississippi
United States	University of Louisville-Brown Cancer Center	Louisville	Kentucky
United States	Allegheny Health Network	Pittsburgh	Pennsylvania
United States	Cancer Center of Central Connecticut	Plainville	Connecticut
United States	Orchard Healthcare Research Inc.	Skokie	Illinois
United States	Toledo Cancer Center	Toledo	Ohio
United States	Carle Cancer Center	Urbana	Illinois
United States	Kansas University Medical Center	Westwood	Kansas
United States	Innovative Clinical Research Institute	Whittier	California
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
BeyondSpring Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Australia,  China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy	Mid-February 2021 (Approximately 2 years after study initiation)
Secondary	ORR	Overall response rate	Approximately 2 years after study initiation.
Secondary	PFS	Progress-free survival	Approximately 2 years after study initiation.
Secondary	Severe Neutropenia	Percent of patients without severe neutropenia on Day 8 of Cycle 1	Day 8 of Cycle 1
Secondary	Month 24 OS Rate	To compare 24-month overall survival rate	24-month after study initiation
Secondary	Month 36 OS Rate	To compare 36-month overall survival rate	36 month after study initiation
Secondary	DoR	Duration of response	Approximately 2 years after study initiation.
Secondary	Quality of Life (EORTC QLQ-C30)	Average Quality of Life score over all observed weeks (scale 0 - 30, higher value represents better outcome)	Approximately 2 years after study initiation.
Secondary	Q-TWiST	To compare the mean difference in quality-adjusted time without symptoms of disease and toxicity	Approximately 2 years after study initiation.
Secondary	QoL (QLQ-LC13)	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)	Approximately 2 years after study initiation.
Secondary	Proportion of patients who received docetaxel	To compare proportion of patients who received docetaxel >8 cycles, >10 cycles, and >12 cycles	During 1st 21-day cycle
Secondary	Month 18 OS Rate	To compare 18-month overall survival rate	18 month after study initiation
Secondary	RDI	To compare relative dose intensity [where dose intensity is defined as dose in mg/m2/week] of docetaxel	First 4, 6, 8, 10, and 12 cycles
Secondary	Month 12 OS Rate	To compare 12-month overall survival rate	12 month after study initiation

External Links

•   BeyondSpring Pharmaceuticals, Inc. Web-site