Plinabulin vs. Pegfilgrastim in Patients With Solid Tumors Receiving Docetaxel Myelosuppressive Chemotherapy Phase 2

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 (20 mg/m^2) versus docetaxel (75 mg/m2) + pegfilgrastim (6 mg).

Detailed Description
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68 patients with advanced and metastatic NSCLC have been randomized with the arm designation and planned intervention as follows: Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) Arm 2: Docetaxel (75 mg/m2) + plinabulin (20 mg/m^2) Arm 3: Docetaxel (75 mg/m2) + plinabulin (10 mg/m^2) Arm 4: Docetaxel (75 mg/m2) + plinabulin (5 mg/m^2)

Official Title
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A Phase 2, Multicenter, Randomized 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


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 or 1. Patients with: Advanced or metastatic NSCLC failing platinum based therapy 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) Myeloid Growth Factors: 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 ANC 1.5 x 109/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 Prothrombin time (PT) and 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, 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 (refer to Section 10.6.2) 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. Receiving any concurrent anticancer therapies. 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 or the patient has detectable Hepatitis B surface Antigen (HBsAg). 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 20 mg/m^2 Plinabulin<br>Docetaxel + 20 mg/m^2 Plinabulin | Drug: Plinabulin<br>* 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>|
| Experimental: 10 mg/m^2 Plinabulin<br>Docetaxel + 10 mg/m^2 Plinabulin | Drug: Plinabulin<br>* 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>|
| Experimental: 5 mg/m^2 Plinabulin<br>Docetaxel + 5 mg/m^2 Plinabulin | Drug: Plinabulin<br>* 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>|
| Active Comparator: 6 mg Pegfilgrastim<br>Docetaxel + 6 mg Pegfilgrastim | 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;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RP3D | establish the Recommended Phase 3 Dose (RP3D) based on PK/PD analysis | At the end of Cycle 4 (each cycle is 21 days) | 
| 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 |
| --- | --- | --- |
| Evaluating the peak plasma concentration (Cmax) of the drug in the blood after administration of a single dose of the drug | a parameter to establish the pharmacokinetic profile of plinabulin | At the end of Cycle 1 (each cycle is 21 days) | 
| Evaluating the time required to achieve peak concentration (Tmax) of the drug after administration | a parameter to establish the pharmacokinetic profile of plinabulin | At the end of Cycle 1 (each cycle is 21 days) | 
| Evaluating Area under curve (AUC) to describe the variation of the drug concentration in blood plasma as a function of time | a parameter to establish the pharmacokinetic profile of plinabulin | At the end of Cycle 1 (each cycle is 21 days) | 
| Evaluating terminal half-time (T1/2) to measure the time it takes for the concentration of the drug in the plasma to be reduced by 50% | a parameter to establish the pharmacokinetic profile of plinabulin | At the end of Cycle 1 (each cycle is 21 days) | 
| Evaluating volume of distribution in the terminal elimination phase (Vz) | a parameter to establish the pharmacokinetic profile of plinabulin | At the end of Cycle 1 (each cycle is 21 days) | 
| Evaluating clearance (Cl) | a parameter to establish the pharmacokinetic profile of plinabulin | At the end of Cycle 1 (each cycle is 21 days) | 
| Evaluating Ambulatory Blood pressure | a parameter to establish the pharmacodynamic profile of plinabulin | At the end of Cycle 1 (each cycle is 21 days) | 
| Evaluating area over the neutropenia curve (AOC) | a parameter to establish the pharmacodynamic profile of plinabulin | At the end of Cycle 1 (each cycle is 21 days) |