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)

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).

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)

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