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

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)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04345900

Enrollment

Registered

2020-04-15

Start date

2017-04-05

Completion date

2018-04-20

Last updated

2024-05-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chemotherapy-induced Neutropenia

Brief summary

To assess the duration of severe neutropenia (DSN) in treatment Cycle 1 in patients treated with docetaxel (75 mg/m2) + plinabulin (5, 10, or 20 mg/m2) or with docetaxel (75 mg/m2) + pegfilgrastim (6 mg). Neutrophils count was to be assessed at baseline (prior to Cycle 1 docetaxel dose) and during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, and 15 (pre-dose on dosing days; times equivalent to pre dose on other days).

Detailed description

55 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)

Interventions

DRUGPlinabulin

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).

DRUGPegfilgrastim

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. At least ≥ 18 years of age (male or female) at the time of signing the informed consent form. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 3. Patients with: Advanced or metastatic NSCLC failing platinum based therapy 4. Pathology confirmation of cancer 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: 1. Prior chemotherapy or radiation treatment 2. Bone marrow involvement by tumor 3. Surgery and/or open wounds within 4 weeks of first administration of study drug 4. Age \> 65 years of age and receiving full chemotherapy dose intensity 6. Life expectancy of 3 months or more. 7. 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 \[AP\] is \> 2.5 x ULN) Serum creatinine ≤ 1.5 x ULN 8. Prothrombin time (PT) and International Normalized Ratio (INR) ≤ 1.5 × upper limit of normal (ULN), activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, based on central laboratory results. 9. Female patients of childbearing potential who had 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 were 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 were sexually active and who were 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, except adjuvant docetaxel given \> 1 year prior to first dose of study drug. 4. 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 required use of strong CYP3A4 inhibitors (refer to Section 10.6.2) 5. 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 Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) treatment-emergent AEs (TEAEs). 6. Received any concurrent anticancer therapies. 7. Received a prior bone marrow or stem cell transplant. 8. Had a co-existing active infection or received systemic anti-infective treatment within 72 hours before the first dose of study drug. 9. Prior radiation therapy within the 4 weeks before the first dose of study drug. 10. Prior use of pegfilgrastim or filgrastim within 4 weeks before the first dose of study drug. 11. 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. 12. 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 despite antihypertensive medication. 13. 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. 14. Any other malignancy requiring active therapy. 15. Known human immunodeficiency virus (HIV) seropositivity. 16. Hepatitis B virsu (HBV) or hepatitis C virus (HCV) infection requiring treatment 17. Female subject who is pregnant or lactating. 18. Unwilling or unable to comply with procedures required in this protocol

Design outcomes

Primary

Measure	Time frame	Description
DSN	At the end of Cycle 1 (each cycle is 21 days)	Duration of Grade 4 neutropenia (ANC \< 0.5 × 109/L)

Secondary

Measure	Time frame	Description
Area Under Curve (AUC)	0, 0.5, 1, 4.5, 24 hours post-dose	A parameter to establish the pharmacokinetic profile of plinabulin to describe the variation of the drug concentration in blood plasma as a function of time
Terminal Half-time (T1/2)	0, 0.5, 1, 4.5, 24 hours post-dose	A parameter to establish the pharmacokinetic profile of plinabulin by measuring the time it takes for the concentration of the drug in the plasma to be reduced by 50%
Volume of Distribution in the Terminal Elimination Phase (Vz)	0, 0.5, 1, 4.5, 24 hours post-dose	A parameter to establish the pharmacokinetic profile of plinabulin by evaluating Vz.
Peak Plasma Concentration (Cmax)	0, 0.5, 1, 4.5, 24 hours post-dose	a parameter to establish the pharmacokinetic profile of plinabulin by evaluating the peak plasma concentration (Cmax) of the drug in the blood after administration of a single dose of the drug
Systolic Blood Pressure	0, 0.5, 1, 4.5, 24 hours post-dose	a parameter to establish the pharmacodynamic profile of plinabulin
Diastolic Blood Pressure	0, 0.5, 1, 4.5, 24 hours post-dose	a parameter to establish the pharmacodynamic profile of plinabulin
Area Over the Neutropenia Curve	0, 0.5, 1, 4.5, 24 hours post-dose	a parameter to establish the pharmacodynamic profile of plinabulin
Clearance (Cl)	0, 0.5, 1, 4.5, 24 hours post-dose	a parameter to establish the pharmacokinetic profile of plinabulin

Countries

China, Russia, Ukraine, United States

Participant flow

Participants by arm

Arm	Count
Arm 1 75 mg/m\^2 Docetaxel + 6 mg Pegfilgrastim	13
Arm 2 75 mg/m\^2 Docetaxel + 20 mg/m\^2 Plinabulin	14
Arm 3 75 mg/m\^2 Docetaxel + 10 mg/m\^2 Plinabulin	14
Arm 4 75 mg/m\^2 Docetaxel + 5 mg/m\^2 Plinabulin	14
Total	55

Baseline characteristics

Characteristic	Total	Arm 1	Arm 2	Arm 4	Arm 3
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	25 Participants	4 Participants	7 Participants	9 Participants	5 Participants
Age, Categorical Between 18 and 65 years	30 Participants	9 Participants	7 Participants	5 Participants	9 Participants
Age, Continuous	61.3 Years STANDARD_DEVIATION 10.24	59.5 Years STANDARD_DEVIATION 8.08	63.0 Years STANDARD_DEVIATION 10.44	64.1 Years STANDARD_DEVIATION 10.33	58.6 Years STANDARD_DEVIATION 11.72
Neutrophil Count at Baseline Visit (Pre-dose)	8.527 10^9 Cells/L STANDARD_DEVIATION 3.2641	9.766 10^9 Cells/L STANDARD_DEVIATION 3.4633	7.498 10^9 Cells/L STANDARD_DEVIATION 2.3376	8.061 10^9 Cells/L STANDARD_DEVIATION 3.9371	8.870 10^9 Cells/L STANDARD_DEVIATION 3.0302
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	13 Participants	3 Participants	4 Participants	3 Participants	3 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	42 Participants	10 Participants	10 Participants	11 Participants	11 Participants
Sex: Female, Male Female	17 Participants	3 Participants	4 Participants	5 Participants	5 Participants
Sex: Female, Male Male	38 Participants	10 Participants	10 Participants	9 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	1 / 13	1 / 14	1 / 14	1 / 14
other Total, other adverse events	11 / 13	12 / 14	12 / 14	12 / 14
serious Total, serious adverse events	2 / 13	2 / 14	2 / 14	2 / 14

Outcome results

Primary

DSN

Duration of Grade 4 neutropenia (ANC \< 0.5 × 109/L)

Time frame: At the end of Cycle 1 (each cycle is 21 days)

Arm	Measure	Value (MEAN)	Dispersion
Arm 1	DSN	0.15 days	Standard Deviation 0.376
Arm 2	DSN	0.36 days	Standard Deviation 0.929
Arm 3	DSN	0.43 days	Standard Deviation 1.089
Arm 4	DSN	0.29 days	Standard Deviation 0.611

Secondary