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

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ClinicalTrials.gov Identifier: NCT03102606
Recruitment Status : Recruiting
First Posted : April 6, 2017
Last Update Posted : March 17, 2020
Sponsor:
Collaborators:
Covance
ICON plc
Information provided by (Responsible Party):
BeyondSpring Pharmaceuticals Inc.

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.

Condition or disease Intervention/treatment Phase
Chemotherapy-induced Neutropenia Drug: Plinabulin Drug: Pegfilgrastim Other: Saline Placebo Other: D5W Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 190 participants
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
Official Title: 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)
Actual Study Start Date : May 29, 2018
Estimated Primary Completion Date : June 1, 2020
Estimated Study Completion Date : July 15, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 0.6 ml Pegfilgrastim + D5W placebo
0.6 ml Pegfilgrastim and 250 ml D5W matching plinabulin
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: D5W Placebo
Placebo 250 ml D5W to match the administration of plinabulin diluted in 250 ml D5W

Experimental: 40 mg Plinabulin + saline placebo
40 mg Plinabulin and 0.6 ml saline matching pegfilgrastim
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

Other: Saline Placebo
Placebo Syringe 0.6 ml Saline to match the 0.6 ml pegfilgrastim administration




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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)

  2. 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

  3. 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

  4. 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

  5. Proportion of patients with thrombocytopenia [ Time Frame: Up to 84 days ]
    Proportion of patients with thrombocytopenia (all grade) during 4 cycles



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. 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

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): NCT03102606


Contacts
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Contact: Ramon Mohanlal, MD, PhD 917-526-1956 rmohanlal@beyondspringpharma.com
Contact: Ilda Boholli, MPH 973-919-4410 iboholli@beyondspringpharma.com

Locations
Show Show 31 study locations
Sponsors and Collaborators
BeyondSpring Pharmaceuticals Inc.
Covance
ICON plc
Investigators
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Principal Investigator: Douglas W. Blayney, MD Stanford University School of Medicine - Cancer Institute
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Responsible Party: BeyondSpring Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03102606    
Other Study ID Numbers: BPI-2358-105 phase 3
First Posted: April 6, 2017    Key Record Dates
Last Update Posted: March 17, 2020
Last Verified: March 2020
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
Keywords provided by BeyondSpring Pharmaceuticals Inc.:
Plinabulin
Pegfilgrastim
Duration of Severe Neutropenia
Bone Pain
Additional relevant MeSH terms:
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Neutropenia
Agranulocytosis
Leukopenia
Leukocyte Disorders
Hematologic Diseases