Plinabulin vs. Pegfilgrastim in Patients With Solid Tumors Receiving Docetaxel Myelosuppressive Chemotherapy Phase 3

Study Overview
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Brief Summary
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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, 6, 7, 8, 9, 10, 15. *Study is officially closed on 08 Feb 2021*

Detailed Description
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Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) + placebo matching plinabulin Arm 2: Docetaxel (75 mg/m2) + plinabulin (40 mg) + placebo matching pegfilgrastim

Official Title
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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)

Conditions
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Chemotherapy-induced Neutropenia

Intervention / Treatment
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* Drug: Plinabulin
* Drug: Pegfilgrastim
* Other: Saline Placebo
* Other: D5W Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least ≥ 18 years of age (male or female) at the time of signing the informed consent form. ECOG performance status of 0 to 1. Patients with: Phase 2 only: • Advanced or metastatic NSCLC failing platinum-based therapy Phase 3 only: Advanced or metastatic breast cancer, who have failed < 5 prior lines of chemotherapy (Note that study treatment may be the first chemotherapy treatment for advanced or metastatic cancer) locally advanced or metastatic NSCLC after platinum therapy failure HRPC (Note that study treatment may be the first chemotherapy treatment) Pathology confirmation of cancer is required. 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): 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 Life expectancy of 3 months or more. The following laboratory results assessed within 14 days prior to study drug administration: Hemoglobin >/= 9 g/dL independent of transfusion or growth factor support Absolute neutrophil count (ANC) >/= 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 </= 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. 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. 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: History of myelogenous leukemia, myelodysplastic syndrome or concomitant sickle cell disease. Received chemotherapy within 4 weeks prior to the first dose of study drug. Received prior docetaxel treatment, except adjuvant docetaxel given > 1 year prior to first dose of study drug Phase 3 only: Received >/= 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). 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 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 CTCAE (v4.03) treatment emergent AEs. Receiving any concurrent anticancer therapies (except continued hormonal treatment). Received a prior bone marrow or stem cell transplant. Has a co-existing active infection or received systemic anti-infective treatment within 72 hours before the first dose of study drug. Prior radiation therapy within the 4 weeks before the first dose of study drug. Prior use of pegfilgrastim or filgrastim within 4 weeks before the first dose of study drug. 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. Significant cardiovascular history: History of myocardial infarction or ischemic heart disease within 1 year (within a window of up to 18 days less than 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. 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. Any other malignancy requiring active therapy. Known human immunodeficiency virus (HIV) seropositivity. 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. Female subject who is pregnant or lactating. Unwilling or unable to comply with procedures required in this protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) + placebo matching plinabulin<br> | Drug: Pegfilgrastim<br>* 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.<br>* Other names: G-CSF;Other: D5W Placebo<br>* Placebo 250 ml D5W to match the administration of plinabulin diluted in 250 ml D5W<br>|
| Experimental: Docetaxel (75 mg/m2) + plinabulin (40 mg) + placebo matching pegfilgrastim<br> | Drug: Plinabulin<br>* 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).<br>* Other names: NPI-2358;Other: Saline Placebo<br>* Placebo Syringe 0.6 ml Saline to match the 0.6 ml pegfilgrastim administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Severe Neutropenia (DSN) | Duration of Grade 4 neutropenia (ANC < 0.5 × 109/L) | At the end of Cycle 1 (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in estimated mean bone pain score | Change in estimated mean bone pain score from pre-dose Day 1 through Day 8 | Day 1 through 8 in Cycle 1 (each cycle is 21 days) | 
| Platelet count in Cycle 1 | Maximum decrease from baseline (prior to Cycle 1 docetaxel dose) | At the end of Cycle 1 (each cycle is 21 days) | 
| Change in Platelet count from baseline in Cycle 1 | Platelet count at least 30% change from baseline at any time during Cycle 1 | Anytime during Cycle 1 (each cycle is 21 days) | 
| Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) > 5 | Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) > 5 from Day 7 through Day 15 | At the end of Cycle 1 (each cycle is 21 days) | 
| Bands count | Bands > 0 after Day 7 through Day 15 | At the end of Cycle 1 (each cycle is 21 days) | 
| Proportion of patients with thrombocytopenia | Proportion of patients with thrombocytopenia (all grade) during 4 cycles | Up to 84 days | 
| Infections | Incidence of infections in cycles 1 to 4 | Cycle 1 to Cycle 4 (each cycle is 21 days) | 
| Antibiotic Use | Incidence of antibiotic use | At the end of Cycle 1 (each cycle is 21 days) | 
| Neutropenia | Grade 4 neutropenia (ANC < 0.5 x 10^9/L) | At the end of Cycle 1 (each cycle is 21 days) | 
| Sepsis | To assess the incidence of sepsis | Cycle 1 to Cycle 4 (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plinabulin, Pegfilgrastim, Duration of Severe Neutropenia, Bone Pain