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

Conditions

Chemotherapy-induced Neutropenia

Keywords

Plinabulin, Pegfilgrastim, Duration of Severe Neutropenia, Bone Pain

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

Detailed description

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

Douglas W. Blayney, Jasmine Hurley, Gabrielle Legaspi, Stephen Duprez, Lan Huang et al. (6 authors)

Journal of Clinical Oncology2023-06-01

10.1200/jco.2023.41.16_suppl.e21163

Abstract P1-12-10: Superior Effectiveness of Plinabulin (Plin) versus No-Treatment for Docetaxel (Doc)-Induced Neutropenia (N) and other Hematologic Complication in Breast Cancer (BC) Patients

Douglas W. Blayney, Jasmine Wells, Stephen Duprez, Gabrielle Legaspi, Lan Huang et al. (6 authors)

Cancer Research2023-03-01

10.1158/1538-7445.sabcs22-p1-12-10

A Bioinformatic Approach to the Clinical Evaluation of Linear Commitment Versus Cloud (Continuum of Low Primed UnDifferentiated) Models for Hematopoiesis Using Plinabulin Clinical Trial Data

Ramon Mohanlal, June Lu, Lan Huang, Lorna Honour, Douglas W. Blayney

Blood2022-11-15

10.1182/blood-2022-167277

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors

Douglas W. Blayney, Ramon Mohanlal, Hryhoriy Adamchuk, Dmitry Valikovich Kirtbaya, Michael Chen et al. (10 authors)

JAMA Network Open2022-01-2724 citations

10.1001/jamanetworkopen.2021.45446

Plinabulin Rapidly (within 24 Hours) Reverses Myelosuppression Induced By Chemotherapy

Douglas W. Blayney, Mengru Chang, Lan Huang, Ramon Mohanlal

Blood2021-11-051 citations

10.1182/blood-2021-150920

Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1.

Douglas W. Blayney, Yuankai Shi, Igor Bondarenko, Stephan Ogenstad, Qingyuan Zhang et al. (8 authors)

Journal of Clinical Oncology2021-05-202 citations

10.1200/jco.2021.39.15_suppl.547

Abstract PS13-34: Differential efficacy of pegfilgrastim (Peg) in patients (pts) with breast cancer (BC) versus other cancer types for the prevention of docetaxel (Doc) chemotherapy-induced neutropenia (CIN)

Douglas W. Blayney, Greg Ginn, Lan Huang, Ramon Mohanlal

Cancer Research2021-02-15

10.1158/1538-7445.sabcs20-ps13-34

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Adults With Non–Small Cell Lung Cancer

Douglas W. Blayney, Qingyuan Zhang, Jifeng Feng, Yanqiu Zhao, Igor Bondarenko et al. (16 authors)

JAMA Oncology2020-09-2431 citations

10.1001/jamaoncol.2020.4429

Head-to-head comparison of the non-G-CSF small molecule single agent (SA) plinabulin with SA pegfilgrastim for the prevention of docetaxel chemotherapy (chemo)-induced neutropenia (CIN) in the protective-1 trial.

Douglas W. Blayney, Lan Huang, Ramon Mohanlal

Journal of Clinical Oncology2020-05-20

10.1200/jco.2020.38.15_suppl.tps7087

Clinical Evidence of Granulocyte-Monocyte Progenitor (GMP) Stem Cell Involvement in Plinabulin's Mechanism of Action (MoA) for the Prevention of Docetaxel (Doc) Chemotherapy (Chemo)-Induced Neutropenia (CIN)

Douglas W. Blayney, Lan Huang, Ramon Mohanlal

Blood2019-11-131 citations

10.1182/blood-2019-127227

Clinical Evidence Against the Continuum of Low-Primed Uncommitted Hematopoietic and Progenitor Cells (CLOUD-HSPC) Concept for Hematopoiesis

Ramon Mohanlal, Douglas W. Blayney, Lan Huang

Blood2019-11-13

10.1182/blood-2019-128563

Comparison of pegfilgrastim (Peg), plinabulin (Plin), and the combination for chemotherapy (Chemo) induced neutropenia (CIN) prevention: Rationale for the combination.

Douglas W. Blayney, Stephan Ogenstad, Yuankai Shi, Qingyuan Zhang, Jifeng Feng et al. (9 authors)

Journal of Clinical Oncology2019-05-20

10.1200/jco.2019.37.15_suppl.e12030

Plinabulin, a Novel Small Molecule in Development for Chemotherapy-Induced-Neutropenia (CIN) Prevention, Mobilizes CD34+ Cells through a Mechanism of Action (MoA) Different from G-CSF and from CXCR4 Inhibition

Douglas W. Blayney, Ene Ette, Stephan Ogenstad, Yuankai Shi, Lihua Du et al. (8 authors)

Blood2018-11-292 citations

10.1182/blood-2018-99-113569

Plinabulin (Plin), a novel non-G-CSF molecule for the revention of chemotherapy-induced neutropenia (CIN), has the potential to positively impact tumor micro environment

Douglas W. Blayney, Stephan Ogenstad, Yuankai Shi, Q. Zhang, Lili Du et al. (7 authors)

Annals of Oncology2018-10-01

10.1093/annonc/mdy300.003

Plinabulin (Plin), a small molecule with anti-cancer activity and a novel mechanism of action (MoA) in docetaxel (Tax)-induced neutropenia: Phase (φ) 2 results from a head-to-head comparison with Pegfilgrastim (Peg).

Douglas W. Blayney, Yuankai Shi, Igor Bondarenko, Qingyuan Zhang, Н. В. Коваленко et al. (12 authors)

Journal of Clinical Oncology2018-05-20

10.1200/jco.2018.36.15_suppl.2528

Interventions

DRUGPlinabulin

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).

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.

OTHERSaline Placebo

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

OTHERD5W Placebo

Placebo 250 ml D5W to match the administration of plinabulin diluted in 250 ml D5W

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Masking description

Plinabulin and pegfilgrastim are each masked using a double-dummy design in phase 3. Docetaxel administration is not masked.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

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: 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) 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): * 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 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. 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 adjuvant docetaxel given \> 1 year prior to first dose of study drug 4. 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). 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 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 CTCAE (v4.03) treatment emergent AEs. 7. Receiving any concurrent anticancer therapies (except continued hormonal treatment). 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 (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. 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

Design outcomes

Primary

Measure	Time frame	Description
Duration of Severe Neutropenia (DSN)	21 Days	Duration of severe neutropenia (ANC \< 0.5 × 109/L)

Secondary

Measure	Time frame	Description
Change in Estimated Mean Bone Pain Score	Day 1 through 8 in Cycle 1 (each cycle is 21 days)	Change in estimated mean bone pain score from pre-dose Day 1 through Day 8. The bone pain scale assessment was based on the validated Wong-Baker Faces® Pain Rating Scale. The pain scale range is from 0 to 10. The severity of pain marked on a scale is from 0 ('no hurt') to 10 ('hurt worst').
Change in Patients With at Least 30% Platelet Count From Baseline in Cycle 1	Anytime during Cycle 1 (each cycle is 21 days)	Patients with platelet count at least 30% change from baseline at any time during Cycle 1
Proportion of Patients With Thrombocytopenia	84 days	Proportion of patients with thrombocytopenia (all grade) during 4 cycles
Proportion of Patients With Neutrophil-to-lymphocyte Ratio (NLR) > 5	15 Days	Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) \> 5 from Day 1 through Day 15
Antibiotic Use	21 Days	Incidence of antibiotic use
Sepsis	84 Days	To assess the incidence of sepsis
Infections	84 Days	Incidence of infections in cycles 1 to 4

Countries

China, Russia, Ukraine, United States

Participant flow

Participants by arm

Arm	Count
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin Arm 1 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. D5W Placebo: Placebo 250 ml D5W to match the administration of plinabulin diluted in 250 ml D5W	53
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim Arm 2 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). Saline Placebo: Placebo Syringe 0.6 ml Saline to match the 0.6 ml pegfilgrastim administration	52
Total	105

Baseline characteristics

Characteristic	Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	19 Participants	12 Participants	31 Participants
Age, Categorical Between 18 and 65 years	34 Participants	40 Participants	74 Participants
Age, Continuous	58.9 years STANDARD_DEVIATION 10.85	57.0 years STANDARD_DEVIATION 10.79	58.0 years STANDARD_DEVIATION 10.81
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	25 Participants	25 Participants	50 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	28 Participants	27 Participants	55 Participants
Sex: Female, Male Female	32 Participants	33 Participants	65 Participants
Sex: Female, Male Male	21 Participants	19 Participants	40 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 53	2 / 52
other Total, other adverse events	49 / 53	51 / 52
serious Total, serious adverse events	6 / 53	8 / 52

Outcome results

Primary

Duration of Severe Neutropenia (DSN)

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

Time frame: 21 Days

Arm	Measure	Value (MEAN)
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Duration of Severe Neutropenia (DSN)	0.246 Days
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Duration of Severe Neutropenia (DSN)	0.770 Days

Secondary

Antibiotic Use

Incidence of antibiotic use

Time frame: 21 Days

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Antibiotic Use	7 Participants
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Antibiotic Use	8 Participants

Secondary

Change in Estimated Mean Bone Pain Score

Change in estimated mean bone pain score from pre-dose Day 1 through Day 8. The bone pain scale assessment was based on the validated Wong-Baker Faces® Pain Rating Scale. The pain scale range is from 0 to 10. The severity of pain marked on a scale is from 0 ('no hurt') to 10 ('hurt worst').

Time frame: Day 1 through 8 in Cycle 1 (each cycle is 21 days)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Change in Estimated Mean Bone Pain Score	2.35 Wong-Baker FACES Pain Scale (range:0-10)	Standard Error 0.178
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Change in Estimated Mean Bone Pain Score	1.69 Wong-Baker FACES Pain Scale (range:0-10)	Standard Error 0.179

Secondary

Change in Patients With at Least 30% Platelet Count From Baseline in Cycle 1

Patients with platelet count at least 30% change from baseline at any time during Cycle 1

Time frame: Anytime during Cycle 1 (each cycle is 21 days)

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Change in Patients With at Least 30% Platelet Count From Baseline in Cycle 1	41 Participants
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Change in Patients With at Least 30% Platelet Count From Baseline in Cycle 1	23 Participants

Secondary

Infections

Incidence of infections in cycles 1 to 4

Time frame: 84 Days

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Infections	8 Participants
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Infections	4 Participants

Secondary

Proportion of Patients With Neutrophil-to-lymphocyte Ratio (NLR) > 5

Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) \> 5 from Day 1 through Day 15

Time frame: 15 Days

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Proportion of Patients With Neutrophil-to-lymphocyte Ratio (NLR) > 5	24 Participants
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Proportion of Patients With Neutrophil-to-lymphocyte Ratio (NLR) > 5	2 Participants

Secondary

Proportion of Patients With Thrombocytopenia

Proportion of patients with thrombocytopenia (all grade) during 4 cycles

Time frame: 84 days

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Proportion of Patients With Thrombocytopenia	19 Participants
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Proportion of Patients With Thrombocytopenia	10 Participants

Secondary

Sepsis

To assess the incidence of sepsis

Time frame: 84 Days

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Docetaxel (75 mg/m2) + Pegfilgrastim (6 mg) + Placebo Matching Plinabulin	Sepsis	0 Participants
Docetaxel (75 mg/m2) + Plinabulin (40 mg) + Placebo Matching Pegfilgrastim	Sepsis	0 Participants

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

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Masking description

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Participants by arm

Baseline characteristics

Adverse events

Outcome results

Duration of Severe Neutropenia (DSN)

Antibiotic Use

Change in Estimated Mean Bone Pain Score

Change in Patients With at Least 30% Platelet Count From Baseline in Cycle 1

Infections

Proportion of Patients With Neutrophil-to-lymphocyte Ratio (NLR) > 5

Proportion of Patients With Thrombocytopenia

Sepsis