Surufatinib Plus Camrelizumab and AS in First Line Treatment of Advanced Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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This study is designed to explore the efficacy and safety of surufatinib combined with camrelizumab and AS (nab-paclitaxel and S-1) as first-line treatment compared with AG (nab-paclitaxel and gemcitabine) in unresectable advanced or metastatic pancreatic cancer.

Detailed Description
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For patients with advanced pancreatic cancer (APC), chemotherapy is still the predominant treatment. The first-line regimens include AG (nab-paclitaxel and gemcitabine) and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). AS (nab-paclitaxel and S-1) was explored and widely used in China especially for those with poor performance. This prospective, randomized controlled phase 1b/2 clinical study was designed to explore the efficacy and safety of surufatinib combined with camrelizumab and AS as first-line treatment compared with AG in APC.

Official Title
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Surufatinib Plus Camrelizumab and AS in First Line Treatment of Advanced Metastatic Pancreatic Cancer: a Prospective, Randomized Controlled Clinical Trial

Conditions
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Pancreatic Cancer, PDAC - Pancreatic Ductal Adenocarcinoma, Pancreas Cancer, Pancreatic Neoplasms

Intervention / Treatment
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* Drug: surufatinib + camrelizumab + nab-paclitaxel + S-1
* Drug: nab-paclitaxel + gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed non resectable, locally advanced or metastatic pancreatic cancer; 18-75 years old (including 18 and 75 years old); No previous anti-tumor treatment for metastatic diseases; Eastern Cooperation Oncology Group (ECOG) performance status of 0-1; Life expectancy ≥ 3 months; At least one measurable lesion according to RECIST version 1.1; Adequate organ and bone marrow functions: Absolute neutrophil count≥1.5x10^9/L; Platelet count≥100x10^9/L; Hemoglobin≥9g/dL; Serum bilirubin<1.5x the upper limit of normal(ULN); Alanine aminotransferase(ALT) and aspartate aminotransferase(AST)<1.5x ULN; Serum creatinine<1.5x ULN; Endogenous creatinine clearance rate ≥ 50ml / min; Women of childbearing age need to take effective contraceptive measures. Exclusion Criteria: Previous treatment with vascular endothelial growth factor receptor (VEGFR) inhibitors or previous use of immune checkpoint inhibitors; With BRCA 1/2 germline mutation; Other untreated or concurrent tumors (except cervical carcinoma in situ, treated basal cell carcinoma or superficial bladder tumor, or if the tumor is cured and there is no evidence of disease for more than 3 years); Have received other systemic anti-tumor treatments, including chemotherapy, signal transduction inhibitors, hormone therapy and immunotherapy within 4 weeks before enrollment; There was central nervous system (CNS) metastasis or previous brain metastasis before enrollment; Liver metastases accounted for half or more of the total liver volume; Have received any surgery or invasive treatment or operation within 4 weeks before enrollment; Have received Local anti-tumor therapy such as hepatic artery interventional embolization, liver metastasis cryoablation or radiofrequency ablation within 4 weeks before enrollment; Uncontrolled malignant ascites; Participated in other clinical trials within 4 weeks before enrollment, and received corresponding experimental drug treatment; Allergic to the study drug or any of its adjuvants; International normalized ratio (INR) > 1.5 or partially activated prothrombin time (APTT) > 1.5 × ULN； The researchers judged clinically significant electrolyte abnormalities; Hypertension that cannot be controlled by drugs, which is specified as: systolic blood pressure ≥ 140 mmHg and / or diastolic blood pressure ≥ 90 mmHg; Patients currently have poorly controlled diabetes (fasting glucose level is greater than CTCAE grade 2 after regular treatment); Patients with dysphagia, active peptic ulcer, intestinal obstruction, active gastrointestinal bleeding, peptic perforation, malabsorption syndrome or uncontrolled intestinal inflammatory diseases; Any disease or state affecting drug absorption before enrollment, or the patient cannot take oral medication; Patients with obvious evidence of bleeding tendency or medical history within 3 months before enrollment, hemoptysis or thromboembolism within 12 months; Cardiovascular diseases with significant clinical significance, including but not limited to acute myocardial infarction, severe / unstable angina pectoris or coronary artery bypass grafting within 6 months before enrollment; Congestive heart failure, New York Heart Association (NYHA) grade > 2; ventricular arrhythmia requiring drug treatment; LVEF (left ventricular ejection fraction) < 50%; Active infection or serious infection that is not controlled by drug (≥CTCAE v5.0 Grade 2）; History of clinically significant hepatic disease, including, but not limited to, known hepatitis B virus (HBV) infection with HBV DNA positive (copies ≥1×10^4/ml or >2000 IU/ml); known hepatitis C virus infection with HCV RNA positive (copies ≥1×10^3/m); hepatitis and cirrhosis; Women who are pregnant or lactating; Urinary protein ≥ ++, and the 24-hour urine protein quantification is greater than 1.0g; Have any other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other conditions that makes the subject not suitable for enrolling according to the judgment of the investigator.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: surufatinib + camrelizumab + nab-paclitaxel + S-1<br> | Drug: surufatinib + camrelizumab + nab-paclitaxel + S-1<br>* phase 1b: surufatinib 200 or 250 mg/d, qd po; camrelizumab: 200mg, I.V., D1, Q3W; nab-paclitaxel: 125mg/m2, I.V., D1, D8, Q3W; S-1: 40-60mg bid, according to BSA, D1-14, Q3W; DLTs will be evaluated at first cycle; phase 2: surufatinib RP2D + camrelizumab + nab-paclitaxel + S-1 when evaluated SD, PR or CR after 4-6 cycles (according to RECIST 1.1), followed by maintenance treatment: surufatinib + camrelizumab + S-1<br>|
| Active Comparator: nab-paclitaxel + gemcitabine<br> | Drug: nab-paclitaxel + gemcitabine<br>* nab-paclitaxel: 125mg/m2, I.V., D1, D8, Q3W; gemcitabine: 1000/m2, ivgtt for more than 30min, D1, D8, Q3W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLTs | Dose-limiting toxicities will be evaluated by the investigators at the first cycle in Ib phase | Up to 21 days after the first dose of surufatinib | 
| RP2D | The RP2D is defined as the dose level of surufatinib chosen by the investigators for the phase II experimental arm, based on DLTs | Up to 21 days after the first dose of surufatinib | 
| ORR | The proportion of patients with a confirmed complete response or partial response | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | The time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first | up to 3 years | 
| DCR | The proportion of patients with a best overall response of confirmed complete or partial response, or stable disease (CR+ PR + SD) | up to 3 years | 
| OS | The time from randomization to death from any reason | up to 3 years | 
| Safety and tolerability by incidence, severity and outcome of adverse events | Safety and tolerance will be evaluated by incidence, severity and outcomes of adverse events (AEs) and categorized by severity in accordance with the NCI CTC AE Version 5.0 | up to 3 years |