A Study of Donafenib Plus S-1 in Treating Patients With Metastatic Pancreatic Cancer After Chemotherapy With Nab-paclitaxel Plus Gemcitabine Regimen

Study Overview
=================
Brief Summary
-----------------
This is a single arm, open label Phase II clinical trial to evaluate the efficacy and safety of donafenib combined with S-1 in treating Patients with metastatic pancreatic cancer after chemotherapy with Nab-paclitaxel plus gemcitabine regimen.

Detailed Description
-----------------
While NG ( Nab-paclitaxel + gemcitabine) is one of the preferred first-line chemotherapy for metastatic pancreatic cancer, we have to investigate possible therapeutic options after NG regimen. In this single arm, open-label clinical trial, metastatic pancreatic cancer patients will be received donafenib and S-1. Treatment repeats every 3 weeks until the disease recurrence or unacceptable toxicity, death or begin a novel therapeutic. The efficacy and safety data will be assessed through OS, ORR, DCR, PFS,TTP and adverse effects as graded by NCI CTC-AE 5.0.

Official Title
-----------------
A Prospective, Phase II, Single-arm Study to Evaluate The Safety and Efficacy of Donafenib Plus S-1 in Treating Patients With Metastatic Pancreatic Cancer After Chemotherapy With Nab-paclitaxel Plus Gemcitabine Regimen

Conditions
-----------------
Metastatic Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: Donafenib
* Drug: S1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed consent and willing to complete the study according to the protocol. Age ≥ 18 years and ≤ 75 years, and there is no limit on the gender ECOG performance scale 0-1; Diagnosed as pancreatic adenocarcinoma by histology and cytology; Treatment of patients with advanced metastatic pancreatic cancer who have failed with NG (Nab-paclitaxel + gemcitabine) regimen(The disease progresses during the course of treatment or within 6 months after the end of treatment, with clear imaging evidence; this does not include patients with intolerable toxicity)； Baseline blood routine and biochemical indexes meet the following criteria: Blood routine examination criteria must be met: (no blood transfusion within 14 days) HB≥90g/L； ANC≥1.5×109/L； PLT≥100×109/L. Biochemical tests are subject to the following criteria: BIL <1.25xULN ； ALT and AST<2.5ULN； Serum creatinine. Less than 1.5 times the upper limit of normal value, Endogenous creatinine clearance>60ml/min ( Cockcroft-Gault formula). Albumin≥28g/L. Blood coagulation indexes are subject to the following criteria: Prothrombin time (PT) and international normalized ratio (INR) ≤1.5 × ULN; Activated partial thromboplastin time（APTT）≤1.5 × ULN. According to the standard of RECIST 1.1, there is at least one imaging measurable lesion; Life expectancy ≥ 3 months; Patients and their families were willing to cooperate with follow-up. Exclusion Criteria: Diagnosis of malignant diseases other than pancreatic cancer within 5 years prior to first administration (excluding cured skin basal cell carcinoma, squamous carcinoma of the skin, and/or resected carcinoma in situ); Medical conditions that affect absorption, distribution, metabolism, or clearance of the study drug (e.g., severe vomiting, chronic diarrhea, intestinal obstruction, absorption disorders, etc.); Patients with brain metastases or pial metastases; Patients with a clear past history of neurological or psychiatric disorders, including epilepsy or dementia; Comorbidities (e.g., severe or uncontrolled hypertension, severe diabetes, and/or thyroid disease) that, in the investigator's judgment, seriously endanger patients' safety or prevent them from completing the study; The patient was currently participating in an interventional clinical study or had been treated with another study drug or study device in the 4 weeks prior to initial dosing; The patient had a history of organ transplantation; Concurrent administration of drugs that may prolong QTc and/or induce Tdp; Patients also take drugs that affect drug metabolism; HIV infection or acute or chronic viral hepatitis (hbSAG positive, HBV-DNA load ≥500IU/ml and/or HCV antibody positive); Excluded patients with serious cardiovascular disease, including grade ≥II cardiac dysfunction (NYHA criteria); Patients with severe gastrointestinal dysfunction (bleeding, infection, obstruction, or diarrhea greater than grade 1) were excluded; Patients with abnormal coagulation function, bleeding tendency, or receiving thrombolytic or anticoagulant therapy were excluded; Patients with a severe arterial thromboembolism event within 6 months were excluded; Excluding women who are pregnant or breast-feeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Donafenib + S-1<br>Donafenib: 200mg po bid； S-1 capsule: According to the body surface area <1.25m2 40mg/d, 1.25   1.5 m2 50 mg/d, > 1.5m2 60mg/d po bid, taking 14 days, stopping for 7 days, 21 days for 1 cycle. | Drug: Donafenib<br>* Donafenib: 200mg po bid.<br>Drug: S1<br>* S-1 capsule: According to the body surface area <1.25m2 40mg/d, 1.25   1.5 m2 50 mg/d, > 1.5m2 60mg/d po bid, taking 14 days, stopping for 7 days, 21 days for 1 cycle.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | To evaluate the overall survival of patients with advanced metastatic pancreatic cancer who have failed with NG (Nab-paclitaxel + gemcitabine) regimen after treatment with Donafenib combined with S-1. | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | To investigate the progression-free survival (PFS) of patients with advanced metastatic pancreatic cancer who have failed with NG (Nab-paclitaxel + gemcitabine) regimen after treatment with Donafenib combined with S-1. | through study completion, an average of 1 year | 
| Overall Response Rate | To evaluate the overall response rate of patients with advanced metastatic pancreatic cancer who have failed with NG (Nab-paclitaxel + gemcitabine) regimen after treatment with Donafenib combined with S-1. | through study completion, an average of 1 year | 
| Incidence of Adverse Events | Adverse events of patients with advanced metastatic pancreatic cancer who have failed with NG (Nab-paclitaxel + gemcitabine) regimen after treatment with Donafenib plus S-1. | through study completion, an average of 1 year |