Study of Irinotecan Liposome Injection-containing Regimens Versus Nab-paclitaxel Plus Gemcitabine in Patients With Previously Untreated, Metastatic Pancreatic Adenocarcinoma

A Multicenter, Randomized, Open-lable, Parallel-controlled, Phase II Study to Evaluate the Differences of Safety and Efficacy of Irinotecan Liposome Injection-containing Regimens Versus Nab-paclitaxel Plus Gemcitabine in Patients With Previously Untreated, Metastatic Pancreatic Adenocarcinoma

This is a multicenter, randomized, open-lable, parallel-controlled phase II study of irinotecan liposome injection-containing regimens versus nab-paclitaxel plus gemcitabine in patients with previously untreated, metastatic pancreatic adenocarcinoma. The purpose of this study is to evaluate the differences of safety and efficacy of irinotecan liposome injection-containing regimens versus nab-paclitaxel plus gemcitabine in patients with previously untreated, metastatic pancreatic adenocarcinoma.

This is a multicentre randomized, open-label, parallel-controlled, phase II study to evaluate the efficacy and safety of irinotecan liposome injection-containing regimens. Eligible patients will be randomly divided into two cohorts at a ratio of 2:1. The patients in cohort 1 (the experimental group) will receive irinotecan liposome injection combined with 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin.The patients in cohort 2 (the control group) will receive nab-paclitaxel plus gemcitabine.

Inclusion Criteria:

1. Age 18 to 70 years old (inclusive), regardless of gender;

2. Histologically or cytologically confirmed unresectable, locally advanced, or metastatic pancreatic adenocarcinoma;

3. At least one measurable lesion according to RECIST 1.1.

4. No prior systemic anti-tumor therapy, except those with disease progression more than 6 months after adjuvant therapy or neoadjuvant therapy;

5. Patients with prior local treatment (radical radiotherapy or radical chemoradiotherapy, etc.) may be enrolled provided that the local treatment does not involve the target lesion, or the target lesion is within the treatment area, but the size has increased more than 20% since the post-treatment evaluation, and also must be completed at least 4 weeks before the first administration of the study drug, palliative decompensated radiotherapy (such as bone metastases) must be completed at least 2 weeks before the first administration of the study drug;

6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1;

7. Life expectancy >3 months;

8. Adverse reactions must recover to grade 1 or baseline according to CTCAE 5.0 (except for toxicity such as alopecia, grade 2 or less sensory neuropathy, etc., which have been judged no safety risk by investigators).

9. Patients should not receive cell growth factors or blood and platelet transfusion within 7 days before the initiate administration of study drug, and laboratory test must meet the following criteria:

   neutrophile count ≥1.5×10^9/L; platelet count ≥100×10^9/L; hemoglobin ≥90 g/L or ≥5.6 mmol/L; serum creatinine ≤1×ULN or creatinine clearance rate must be ≥ 50 mL/min when serum creatinine >1.0×ULN; total bilirubin ≤1.5×ULN; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN or ≤5×ULN if intrahepatic lesions exist; Albumin ≥3 g/dL.

10. Activated Partial Thromboplastin Time (APTT), International Normalized Ratio (INR) and prothrombin time (PT) ≤1.5 × ULN for patients not receiving therapeutic anticoagulation.

11. According to the related guidelines, patients with HBV DNA or HBsAg and/or anti-HBC positive must receive prophylactic treatment (at least one week before the initial administration of the study drug) and take antiviral drugs in stable dose (e.g., entecavir, tenofovir, or lamivudine; No adefovir or interferon are allowed) at study entry with planned monitoring and management, including baseline HBV DNA levels. Patient receiving active hepatitis C virus (HCV) treatment must use astable dose of drugs at study entry and be subject to planned monitoring and management according to antiviral drug guidelines;

12. Female patients with reproductive potential must agree to use adequate contraception from the signing of informed consent to at least 6 months after the study completion and have a negative serum pregnancy test within 3 days before enrollment, and must be non-lactating. Male patients must agree to use medically approved contraception during the study period and for 6 months after the study completion;

13. Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

1. Patients with acinar cell carcinoma, pancreatoblastoma, solid pseudopapillary tumor and pancreatic neuroendocrine tumor;
2. Patients with definitive diagnosis of CNS metastasis;
3. Patients with hepatic encephalopathy at screening;
4. Patients with clinically symptomatic ascites requiring puncture or drainage or who have received ascites drainage within the past 3 months, except for those with only a small amount of ascites on imaging but no clinical symptoms;
5. Uncontrolled third lacunar effusion other than ascites (e.g., large pleural or pericardial effusion) within 4 weeks before the first administration of the test drug;
6. Previous malignancies in the past five years (except radically resected and non-recurring basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder carcinoma, local prostate carcinoma, carcinoma in situ of cervical, or other carcinoma in situ);
7. Patients with partial or complete biliary obstruction who has not relieved by active treatment;
8. History of serious cardiovascular disease, including but not limited to:

1) Acute myocardial infarction, unstable angina pectoris, coronary angioplasty, stroke, severe pulmonary embolism; 2) New York Heart Association class grade III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50%; 3) Poorly controlled hypertension (systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure≥ 95 mmHg) with optimal treatment; 4) Ventricular arrhythmia; 5) Patients with prolonged QT/QTc interval in baseline electrocardiogram (ECG) (QTcF > 480 ms, Fridericia formula: QTcF = QT/(RR^0.33), RR = 60/heart rate); 6) Patients with clinically significant abnormal electrocardiogram (ECG) according to the investigator's assessment.

9.Patients with uncontrolled active bleeding.

10.Patients with known interstitial lung disease;

11.Patients with known peripheral neuropathy (CTCAE grade 3 or 4);

12.Patients with severe lung, liver, kidney, endocrine, immune system, skin or musculoskeletal diseases within 3 months prior to the first dose and who are not suitable for enrollment in the opinion of the investigator;

13.Patients who are at risk of active infection or have active infection that may affect the results of the study (such as severe pneumonia requiring hospitalization, bacteremia, acute bacterial infection, infectious complications, tuberculosis, active HIV infection, etc.) or who, in the judgment of the investigator, are not suitable for participation in this clinical trial. Active hepatitis B virus is defined as HBV DNA≥10^4 copies or ≥ 2000 IU/mL; active hepatitis C virus or active HIV infection is defined as HCV-RNA positive;

14.Gastrointestinal diseases of clinical significance, such as bleeding, inflammation, obstruction, >grade 1 diarrhea, malabsorption syndrome, diseases significantly affecting gastrointestinal function, gastric or small bowel resection, etc;

15.Patients with known to have dihydropyrimidine dehydrogenase (low activity) or deficiency;

16.Patients with definite Gilbert syndrome;

17.History of explicit neurological or psychiatric disorders, including epilepsy or dementia;

18.Patients with known alcohol or drug dependence.

19.Patients who have concomitant use of strong CYP3A4 inducers within 2 weeks prior to the first dose, or strong CYP3A4 inhibitors or strong UGT1A1 inhibitors within 1 week prior to the first dose;

20.Patients who have required systemic glucocorticoids (prednisone >10 mg/day or equivalent dose of the similar drugs) or other immunosuppressive agents within 14 days before the first dose of the study drug. Except for treatment with local, ocular, intra-articular, intranasal, and inhaled glucocorticoids in the absence of active autoimmune disease, short-term preventive treatment with glucocorticoids (e.g., prevention of contrast allergy);

21.Patients who have major organ surgery (except for needle biopsy, central venous catheterization, port-cath, stenting to relieve biliary obstruction, and percutaneous hepatic biliary drainage, cholecystostomy) or selective operation plan were performed within 4 weeks before the first dose of the study drug;

22.Patients with known allergy to irinotecan liposome injection, other liposome products, oxaliplatin, 5-fluorouracil, leucovorin, Nab-paclitaxel, other albumin products, gemcitabine or any of the ingredients in the above products.;

23. Patients who are not suitable for this study as determined by the investigator.