Safety and Efficacy Study of Nab-paclitaxel Plus Gemcitabine in Chinese Patients With Metastatic Pancreatic Cancer

This is a Phase 2 trial in China to evaluate the safety and efficacy of the combination of nab-paclitaxel and gemcitabine administered in patients diagnosed with metastatic pancreatic adenocarcinoma. This study is designed to be a Chinese bridging study to complement the Global pivotal study (CA-046).

The study consists of three parts: (1) Dose evaluation; (2) Single arm to evaluate efficacy following an optimal Simon two-stage design; and (3) Randomized 2-arm to evaluate the efficacy and safety of nab-paclitaxel plus gemcitabine versus gemcitabine alone. These 3 parts will be carried out sequentially. The Part 3 randomized 2-arm portion will only be carried out if deemed necessary per protocol.

Inclusion criteria

• Patient has definitive histologically or cytologically confirmed metastatic pancreatic adenocarcinoma (Islet cell neoplasms are excluded) that is measurable by Response Evaluation criteria for solid tumors (RECIST V1.0)
• Patients must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic pancreatic cancer. Prior treatment with 5-fluorouracil (5-FU) or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present. Patients having received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting are not eligible for this study
• Patient has a Karnofsky performance status (KPS) ≥ 70
• Initial diagnosis of metastatic disease must have occurred ≤ 6 weeks prior to starting Cycle 1 Day 1. NOTE: the clock for this time interval starts with the date of last evaluation confirming pancreatic metastatic disease (either biopsy or imaging results)
• Patients should be asymptomatic for jaundice prior to Cycle 1 Day 1. Significant or symptomatic amounts of ascites should be drained prior to Cycle 1 Day 1. Pain symptoms should be stable and should not require modifications in analgesic management prior to Cycle 1 Day 1
• Patient has adequate blood counts at screening (obtained ≤ 14 days prior to starting Cycle 1 Day 1):

• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L;
• Platelet count ≥ 100,000/mm^3 (100 × 10^9/L);
• Hemoglobin (Hgb) ≥ 9 g/dL
• Patient has the following blood chemistry levels at Screening (obtained ≤ 14 days prior to starting Cycle 1 Day 1):

• Aspartate aminotransferase (SGOT) and alanine transaminase (SGPT) are ≤ 2.5 upper limit of normal (ULN) range, unless liver metastases are clearly present, then ≤ 5 × upper limit of normal (ULN) range is allowed
• Total bilirubin ≤ upper limit of normal range
• Serum creatinine within normal limits or calculated clearance ≥ 60 mL/min/1.73 m^2 for patients with serum creatinine levels above or below the institutional normal value. If using creatinine clearance, actual body weight should be used for calculating creatinine clearance (eg, using the Cockcroft-Gault formula). For patients with a body mass index (BMI) > 30 kg/m^2, lean body weight should be used instead.
• The patient has acceptable coagulation studies (obtained ≤14 days prior to starting Cycle 1 Day 1) as demonstrated by prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits (WNL) ±15%.
• The patient has no clinically significant abnormalities in urinalysis results (obtained ≤14 days prior to starting Cycle 1 Day 1).
• Male or non-pregnant and non-lactating female, and ≥ 18 years of age at the time of signing the informed consent document.

• If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative pregnancy test (e.g. serum β-subunit of human chorionic gonadotropin (β-hCG) documented prior to the first administration of study drug.
• If sexually active, the patient must agree to use contraception considered adequate and appropriate by the Investigator during the period of administration of study drug. In addition, male and female patients must utilize contraception after the end of treatment as recommended in the product's
• Patient has been informed about the nature of the study, and has agreed to participate in the study, and signed the Informed Consent Form prior to participation in any study-related activities.
• Able to adhere to the study visit schedule and other protocol requirements.

Exclusion criteria

• Patient has known brain metastases
• Patient has only locally advanced disease.
• Patient has a ≥ 20% decrease in serum albumin level between Screening visit and within 72 hours prior to Cycle 1 Day 1.
• History of malignancy in the last 5 years (including chronic leukemias). Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Patients with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 5 years.
• Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
• Patient has known infection with human immunodeficiency virus, and/or active infection with hepatitis B, or hepatitis C (patients with known historical infection with hepatitis B or C should be discussed with the Sponsor).
• Patient has undergone major surgery, other than diagnostic surgery (ie, surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Day 1 of treatment in this study.
• Patient that has a history of a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or electrocardiogram (ECG) abnormality, cerebrovascular accident, transient ischemic attack, seizure disorder or clinically significant cardiac dysrhythmia or ECG abnormality, within 6 months prior to Cycle 1 Day 1
• Patient has a history of allergy or hypersensitivity to any of the study drugs or any of their excipients, or the patient exhibits any of the adverse events .
• History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa).
• Patients with a history of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies.
• Patient has any condition, including serious medical risk factors, medical conditions, laboratory abnormalities or psychiatric disorders, which could compromise the patient's safety or the study data integrity.
• Patient is enrolled in any other clinical protocol or investigational trial with an interventional agent or assessments that may interfere with study procedures.
• Patient is unwilling or unable to comply with study procedures, or is planning to take vacation for 7 or more consecutive days during the treatment phase of the study.