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Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC (DUBLIN-3)

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ClinicalTrials.gov Identifier: NCT02504489
Recruitment Status : Active, not recruiting
First Posted : July 22, 2015
Last Update Posted : April 19, 2021
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Drug: Docetaxel + Plinabulin (DP) Drug: Docetaxel (D) Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 559 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Masking Description: placebo
Primary Purpose: Treatment
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
Actual Study Start Date : December 2015
Actual Primary Completion Date : March 23, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Docetaxel

Arm Intervention/treatment
Active Comparator: 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.
Drug: Docetaxel (D)
Docetaxel 75 mg/m2 IV
Other Name: Taxotere

Experimental: 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.
Drug: Docetaxel + Plinabulin (DP)
Docetaxel 75 mg/m2 IV + Plinabulin 30 mg/m2
Other Name: BPI-2358, NPI-2358

Drug: Docetaxel (D)
Docetaxel 75 mg/m2 IV
Other Name: Taxotere




Primary Outcome Measures :
  1. Overall Survival [ Time Frame: Mid-February 2021 (Approximately 2 years after study initiation) ]
    Overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy


Secondary Outcome Measures :
  1. ORR [ Time Frame: Approximately 2 years after study initiation. ]
    Overall response rate

  2. PFS [ Time Frame: Approximately 2 years after study initiation. ]
    Progress-free survival

  3. Severe Neutropenia [ Time Frame: Day 8 of Cycle 1 ]
    Percent of patients without severe neutropenia on Day 8 of Cycle 1

  4. Month 24 OS Rate [ Time Frame: 24-month after study initiation ]
    To compare 24-month overall survival rate

  5. Month 36 OS Rate [ Time Frame: 36 month after study initiation ]
    To compare 36-month overall survival rate

  6. DoR [ Time Frame: Approximately 2 years after study initiation. ]
    Duration of response

  7. Quality of Life (EORTC QLQ-C30) [ Time Frame: Approximately 2 years after study initiation. ]
    Average Quality of Life score over all observed weeks (scale 0 - 30, higher value represents better outcome)

  8. Q-TWiST [ Time Frame: Approximately 2 years after study initiation. ]
    To compare the mean difference in quality-adjusted time without symptoms of disease and toxicity

  9. QoL (QLQ-LC13) [ Time Frame: 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)

  10. Proportion of patients who received docetaxel [ Time Frame: During 1st 21-day cycle ]
    To compare proportion of patients who received docetaxel >8 cycles, >10 cycles, and >12 cycles

  11. Month 18 OS Rate [ Time Frame: 18 month after study initiation ]
    To compare 18-month overall survival rate

  12. RDI [ Time Frame: 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

  13. Month 12 OS Rate [ Time Frame: 12 month after study initiation ]
    To compare 12-month overall survival rate



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02504489


Locations
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Sponsors and Collaborators
BeyondSpring Pharmaceuticals Inc.
Additional Information:
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Responsible Party: BeyondSpring Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT02504489    
Other Study ID Numbers: BPI-2358-103
First Posted: July 22, 2015    Key Record Dates
Last Update Posted: April 19, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Docetaxel
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action