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Plinabulin vs. Pegfilgrastim in Patients With Solid Tumors Receiving Docetaxel Myelosuppressive Chemotherapy Phase 3 (Protective-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03102606
Recruitment Status : Active, not recruiting
First Posted : April 6, 2017
Last Update Posted : July 9, 2020
Sponsor:
Collaborators:
Covance
ICON plc
Information provided by (Responsible Party):
BeyondSpring Pharmaceuticals Inc.

Tracking Information
First Submitted Date  ICMJE March 6, 2017
First Posted Date  ICMJE April 6, 2017
Last Update Posted Date July 9, 2020
Actual Study Start Date  ICMJE May 29, 2018
Estimated Primary Completion Date October 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 18, 2018)
Duration of Severe Neutropenia (DSN) [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
Duration of Grade 4 neutropenia (ANC < 0.5 × 109/L)
Original Primary Outcome Measures  ICMJE
 (submitted: March 30, 2017)
Duration of Severe Neutropenia (DSN) [ Time Frame: Duration of Grade 4 neutropenia assessed once within the first 21-day cycle ]
Duration of Grade 4 neutropenia (ANC < 0.5 × 109/L)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2018)
  • Platelet count in Cycle 1 [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
    maximum decrease from baseline (prior to Cycle 1 docetaxel dose)
  • Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) > 5 [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
    Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) > 5 from Day 7 through Day 15
  • AUC using the trapezoidal quadrature method for bone pain [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
    based on the pain score from the patient bone pain scale from Day 1 through Day 8
  • Change in estimated mean bone pain score [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
    Change in estimated mean bone pain score from pre-dose Day 1 through Day 8
  • Proportion of patients with thrombocytopenia [ Time Frame: Up to 84 days ]
    Proportion of patients with thrombocytopenia (all grade) during 4 cycles
Original Secondary Outcome Measures  ICMJE
 (submitted: March 30, 2017)
  • Incidence of Grade 4 neutropenia [ Time Frame: Duration of the study treatment period (84 days) ]
    Grade 4 neutropenia (ANC < 0.5 × 109/L)
  • Incidence of Febrile Neutropenia (FN) [ Time Frame: Duration of the study treatment period (84 days) ]
    FN = ANC < 0.5 × 10**9/L and body temperature ≥ 38.3°C
  • Health-related QoL questionnaire evaluated with EORTC QLQ-C30 [ Time Frame: Duration of the study treatment period (84 days) ]
    Quality of Life Measurement
  • Neutrophil Nadir [ Time Frame: The neutrophil nadir is identified once during the first 21-day cycle ]
    Minimum neutrophil count during Cycle 1
  • Incidence of docetaxel treatment modification [ Time Frame: Duration of the study treatment period (84) days ]
    Modification of docetaxel administration
  • Bone pain [ Time Frame: Duration of the study treatment period (84 days) ]
    Bone pain inventory - Short Form
  • Incidence of Hospitalizations due to FN [ Time Frame: Duration of the study treatment period (84 days) ]
    FN = ANC < 0.5 × 10**9/L and body temperature ≥ 38.3°C
  • Incidence of documented infections [ Time Frame: Duration of the study treatment period (84 days) ]
    Percentage of patients in with documented infections
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Plinabulin vs. Pegfilgrastim in Patients With Solid Tumors Receiving Docetaxel Myelosuppressive Chemotherapy Phase 3
Official Title  ICMJE A Phase 3, Multicenter, Randomized, Double Blind, Study to Evaluate Duration of Severe Neutropenia With Plinabulin Versus Pegfilgrastim in Patients With Solid Tumors Receiving Docetaxel Myelosuppressive Chemotherapy (Protective 1)
Brief Summary To assess Duration of Severe Neutropenia (DSN) in treatment Cycle 1 in patients with advanced or metastatic breast cancer, who have failed >/= 1 but < 5 prior lines of chemotherapy; locally advanced or metastatic non small cell lung cancer (NSCLC) after platinum therapy failure; or hormone refractory (androgen independent) metastatic prostate cancer treated with docetaxel (75 mg/m2) + plinabulin (40 mg) versus docetaxel (75 mg/m2) + pegfilgrastim (6 mg). Neutrophils count will be assessed at baseline; Pre dose during Cycle 1, Day 1, 2, 5, 6, 7, 8, 9, 10, 15.
Detailed Description

This is a multicenter, double-blind, randomized study. Approximately 190 patients will be enrolled in this study.

All patients will receive docetaxel at a dose of 75 mg/m2. Pn Phase 3, patients with one of the following will be enrolled: advanced or metastatic breast cancer, who have failed ≥ 1 but < 5 prior lines of chemotherapy; locally advanced or metastatic NSCLC after platinum therapy failure; or hormone refractory (androgen independent) metastatic prostate cancer.

The eligibility of all patients will be determined during a 28-day screening period.

Approximately 150 patients are planned to be enrolled in the Phase 3 with one of the following diagnosis: advanced or metastatic breast cancer, who have failed ≥ 1 but < 5 prior lines of chemotherapy; locally advanced or metastatic NSCLC after platinum therapy failure; or hormone refractory (androgen independent) metastatic prostate cancer. Each eligible patient will be stratified according to his or her diagnosis (advanced or metastatic breast cancer, NSCLC, or HRPC). Patients will be randomly assigned with equal probability (1:1 ratio) or 75:75, with the arm designation and planned intervention as follows:

Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) + placebo matching plinabulin

Arm 2: Docetaxel (75 mg/m2) + plinabulin (40 mg) + placebo matching pegfilgrastim

In order to facilitate balanced treatment arms with respect to cancer type, once either arm reaches at least 1/3 (of total) of patients with that cancer type, it will be closed to that cancer type and enrollment will continue for patients with the other cancer types, up to the planned maximum number of patients.

Data from all patients receiving the RP3D plinabulin dose in Phase 2 and Phase 3 will not be pooled for assessing the primary and secondary study endpoints, but analyzed separately.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

Plinabulin and pegfilgrastim are each masked using a double-dummy design in phase 3.

Docetaxel administration is not masked.

Primary Purpose: Supportive Care
Condition  ICMJE Chemotherapy-induced Neutropenia
Intervention  ICMJE
  • Drug: Plinabulin
    Plinabulin (BPI-2358) is a synthetic, low molecular weight, new chemical entity that belongs to the diketopiperazine class of compounds. Plinabulin is intended for intravenous (IV) infusion and is diluted in D5W and administered for 30 minutes (± 5 minutes).
    Other Names:
    • BPI-2358
    • NPI-2358
  • Drug: Pegfilgrastim
    PEGFILGRASTIM is a long-acting granulocyte colony-stimulating factor that stimulates the growth of neutrophils, to reduce the incidence of fever and infection in patients with certain types of cancer who are receiving chemotherapy that affects the bone marrow.
    Other Names:
    • Neulasta
    • G-CSF
  • Other: Saline Placebo
    Placebo Syringe 0.6 ml Saline to match the 0.6 ml pegfilgrastim administration
  • Other: D5W Placebo
    Placebo 250 ml D5W to match the administration of plinabulin diluted in 250 ml D5W
Study Arms  ICMJE
  • Active Comparator: 0.6 ml Pegfilgrastim + D5W placebo
    0.6 ml Pegfilgrastim and 250 ml D5W matching plinabulin
    Interventions:
    • Drug: Pegfilgrastim
    • Other: D5W Placebo
  • Experimental: 40 mg Plinabulin + saline placebo
    40 mg Plinabulin and 0.6 ml saline matching pegfilgrastim
    Interventions:
    • Drug: Plinabulin
    • Other: Saline Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: December 20, 2019)
190
Original Estimated Enrollment  ICMJE
 (submitted: March 30, 2017)
170
Estimated Study Completion Date  ICMJE November 5, 2020
Estimated Primary Completion Date October 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. At least ≥ 18 years of age (male or female) at the time of signing the informed consent form.
  2. ECOG performance status of 0 to 1.
  3. Patients with:

    • Advanced or metastatic breast cancer, who have failed </= 1 but < 5 prior lines of chemotherapy
    • Locally advanced or metastatic NSCLC after platinum therapy failure
    • Hormone refractory (androgen independent) metastatic prostate cancer (HRPC).
  4. Pathology confirmation of cancer is required.
  5. Patients with ≥ 1 of the following risk factors, at the initiation of docetaxel chemotherapy, that would require neutropenia prophylaxis per National Comprehensive Cancer Network (NCCN) guidelines (version 2, 2016) Myeloid Growth Factors (refer to Appendix C):

    • Prior chemotherapy or radiation treatment
    • Bone marrow involvement by tumor
    • Surgery and/or open wounds within 4 weeks of first administration of study drug
    • Age > 65 years of age and receiving full chemotherapy dose intensity
  6. Life expectancy of 3 months or more.
  7. The following laboratory results provided by the central laboratory within 14 days prior to study drug administration:

    • Hemoglobin >/= 9 g/dL independent of transfusion or growth factor support
    • Absolute neutrophil count >/= 1.5 x 10**9/L independent of growth factor support
    • Serum total bilirubin </= 1.5 times the upper limit normal (ULN), unless the patient has a diagnosis of Gilbert's disease in which case direct bilirubin < t 1.5 times ULN of the direct bilirubin. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 2.5 x ULN (</= 1.5 x ULN if alkaline phosphatase is > 2.5 x ULN)
    • Serum creatinine </= 1.5 x ULN

    Note: Results are from the central laboratory. Local laboratory results may be accepted on a case by case basis after discussion with the Medical Monitor, however in this case central laboratories must also be taken within the screening time window.

  8. Prothrombin time (PT)/International Normalized Ratio (INR) ≤ 1.5 × upper limit of normal (ULN), activated partial thromboplastin time (PTT) ≤ 1.5 × ULN, based on central laboratory results.
  9. Female subjects of childbearing potential have a negative pregnancy test at screening. 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 amenorrhoeic 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.

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

Exclusion Criteria:

  1. History of myelogenous leukemia, myelodysplastic syndrome or concomitant sickle cell disease.
  2. Received chemotherapy within 4 weeks prior to the first dose of study drug.
  3. Received prior docetaxel treatment, except if docetaxel received as adjuvant therapy for breast cancer > 1 year before the first dose of study drug.
  4. Received no prior chemotherapy or >/= 5 lines of cytotoxic chemotherapy for advanced or metastatic breast cancer (adjuvant chemotherapy will count as one line of chemotherapy, and any hormonal or biological, non conjugate therapy [e.g., trastuzumab] will not count as a line of therapy).
  5. Current use of strong cytochrome P450 (CYP) 3A4 inhibitors, within 3 days of the first administration of study drug, and 7 days after treatment with taxanes OR requires use of strong CYP3A4 inhibitors (refer to Section 11.6.2)
  6. Received an investigational agent or tumor vaccine within 2 weeks before the first dose of study drug; patients must have recovered from toxicity of prior treatment and have no > Grade 1 treatment emergent AEs.
  7. Receiving any concurrent anticancer therapies.
  8. Received a prior bone marrow or stem cell transplant.
  9. Has a co-existing active infection or received systemic anti-infective treatment within 72 hours before the first dose of study drug.
  10. Prior radiation therapy within the 4 weeks before the first dose of study drug.
  11. Prior use of pegfilgrastim or filgrastim within 4 weeks before the first dose of study drug.
  12. Presence of any serious or uncontrolled illness including, but not limited to: uncontrolled diabetes, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled arterial thrombosis, symptomatic pulmonary embolism, or psychiatric illness that would limit compliance with study requirements, or any other conditions that would preclude the patient from study treatment as per the discretion of the Investigator.
  13. Significant cardiovascular history:

    • History of myocardial infarction or ischemic heart disease within 1 year before first study drug administration;
    • Uncontrolled arrhythmia;
    • History of congenital QT prolongation;
    • Electrocardiogram (ECG) findings consistent with active ischemic heart disease;
    • New York Heart Association Class III or IV cardiac disease;
    • Uncontrolled hypertension: blood pressure consistently >150 mm Hg systolic and > 100 mm Hg diastolic in spite of antihypertensive medication.
  14. 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.
  15. Any other malignancy requiring active therapy.
  16. Known human immunodeficiency virus (HIV) seropositivity.
  17. Active Hepatitis B virus (HBV) infection which requires antiviral treatment. Patients with detectable Hepatitis B surface Antigen (HBsAg) may be eligible provided the patient has a negative viral load. Patients with a positive HBsAg must have a negative viral load before each chemotherapy administration. Hepatitis B surface antibody (anti HBs) without detectable HBsAg does NOT exclude patients from the study. Hepatitis C infection (Hepatitis C antibody reactive) which requires treatment also excludes patients from the study.
  18. Female subject who is pregnant or lactating.
  19. Unwilling or unable to comply with procedures required in this protocol
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China,   Russian Federation,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03102606
Other Study ID Numbers  ICMJE BPI-2358-105 phase 3
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party BeyondSpring Pharmaceuticals Inc.
Study Sponsor  ICMJE BeyondSpring Pharmaceuticals Inc.
Collaborators  ICMJE
  • Covance
  • ICON plc
Investigators  ICMJE
Principal Investigator: Douglas W. Blayney, MD Stanford University School of Medicine - Cancer Institute
PRS Account BeyondSpring Pharmaceuticals Inc.
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP