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

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)

Sponsors

Lead Sponsor: BeyondSpring Pharmaceuticals Inc.

Collaborator: Covance
ICON plc

Source 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.

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.

Overall Status Active, not recruiting
Start Date May 29, 2018
Completion Date November 5, 2020
Primary Completion Date October 30, 2020
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Duration of Severe Neutropenia (DSN) At the end of Cycle 1 (each cycle is 21 days)
Secondary Outcome
Measure Time Frame
Platelet count in Cycle 1 At the end of Cycle 1 (each cycle is 21 days)
Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) > 5 At the end of Cycle 1 (each cycle is 21 days)
AUC using the trapezoidal quadrature method for bone pain At the end of Cycle 1 (each cycle is 21 days)
Change in estimated mean bone pain score At the end of Cycle 1 (each cycle is 21 days)
Proportion of patients with thrombocytopenia Up to 84 days
Enrollment 190
Condition
Intervention

Intervention Type: Drug

Intervention Name: Plinabulin

Description: 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).

Arm Group Label: 40 mg Plinabulin + saline placebo

Intervention Type: Drug

Intervention Name: Pegfilgrastim

Description: 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.

Arm Group Label: 0.6 ml Pegfilgrastim + D5W placebo

Intervention Type: Other

Intervention Name: Saline Placebo

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

Arm Group Label: 40 mg Plinabulin + saline placebo

Intervention Type: Other

Intervention Name: D5W Placebo

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

Arm Group Label: 0.6 ml Pegfilgrastim + D5W placebo

Eligibility

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

- 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 2.5 x ULN)

- Serum creatinine

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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Douglas W. Blayney, MD Principal Investigator Stanford University School of Medicine - Cancer Institute
Location
Facility:
Synergy Hematology-Oncology Medical Associates | Los Angeles, California, 90048, United States
Stanford University School of Medicine - Cancer Institute | Stanford, California, 94305-5827, United States
Innovative Clinical Research Institute | Whittier, California, 90603, United States
Mid Florida Hematology and Oncology Center | Orange City, Florida, 32763, United States
Cancer Center of Middle Georgia | Dublin, Georgia, 31021, United States
Quincy Medical Group | Quincy, Illinois, 62301, United States
Hematology/Oncology of the North Shore | Skokie, Illinois, 60076, United States
Henry Ford Hospital | Detroit, Michigan, 48202, United States
North Shore Hematology/Oncology Associates, P.C. | East Setauket, New York, 11733, United States
Gettysburg Cancer Center | Gettysburg, Pennsylvania, 17325, United States
Heilongjiang Cancer Hospital | Harbin, Heilongjiang, 150000, China
Jiangsu Cancer Hospital | Nanjing, Jiangsu, 210000, China
Arkhangelsk Regional Clinical Oncology Dispensary | Arkhangelsk, 163045, Russian Federation
"Llc ""Evimed | Chelyabinsk, 454048, Russian Federation
Kursk Regional Clinical Oncology Dispensary | Kursk, 305524, Russian Federation
Clinical Oncology Dispensary | Omsk, 644013, Russian Federation
"Medical University "Reaviz" | Samara, 443001, Russian Federation
SBI of Healthcare "Oncology Dispensary #2" Ministry of Healthcare of Krasnodar Region | Sochi, 354067, Russian Federation
Volgograd Regional Clinical Oncology Dispensary | Volgograd, 400138, Russian Federation
Chernihiv Regional Oncological Center | Chernihiv, 14029, Ukraine
Dnipropetrovsk City Multifunctional Hospital | Dnepropetrovsk, 49102, Ukraine
Prykarpatskiy Regional Oncological Center | Ivano-Frankivs'k, 76000, Ukraine
Regional Oncology Center | Kharkiv, 61070, Ukraine
Communal Institution of Kherson Regional Council "Kherson regional oncological dispensary" | Kherson, 73000, Ukraine
Kyiv City clinical oncology centre | Kiev, 03115, Ukraine
Kirovograd Regional Oncological Center | Kropyvnytskyi, 25011, Ukraine
Treatment and Prevention Institution "Volyn Regional Oncology Dispensary | Lutsk, 43018, Ukraine
Lviv State Oncological Regional Treatment and Preventive Center | Lviv, 79031, Ukraine
Municipal Institution "Sumy Regional Clinical Oncology Dispensary | Sumy, 40022, Ukraine
Zakarpattia Regional Clinical Oncology Center | Uzhgorod, 88000, Ukraine
Vinnitsa Regional Clinical Oncological Dispenser | Vinnytsya, 21029, Ukraine
Location Countries

China

Russian Federation

Ukraine

United States

Verification Date

March 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: 0.6 ml Pegfilgrastim + D5W placebo

Type: Active Comparator

Description: 0.6 ml Pegfilgrastim and 250 ml D5W matching plinabulin

Label: 40 mg Plinabulin + saline placebo

Type: Experimental

Description: 40 mg Plinabulin and 0.6 ml saline matching pegfilgrastim

Acronym Protective-1
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Supportive Care

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.

Source: ClinicalTrials.gov