Phase II Study of Sufantinib Combined With AG Versus AG First-line in the Treatment of LAPC or mPC

This is a single-center, open-label randomized controlled Phase II clinical study to observe and evaluate the efficacy and safety of Sovantinib in combination with AG versus AG first-line treatment in patients with locally advanced or metastatic pancreatic cancer.

According to the literature analysis, the mPFS of gemcitabine combined with albumin-binding paclitaxel in first-line treatment of metastatic pancreatic cancer was 3.56 months in historical controlled studies, and the expected PFS of soantinib combined with AG regimen increased from 2.06 months to 4.5 months after 2 cycles of AG regimen. Follow-up time was 12 months and enrollment time was 18 months. α=0.05 and β=0.2 were used for bilateral test, and the PASS 22 software was used for analysis. The sample size of AG group in the control group was 29 cases, and that of AG combined with Solvatinib in the experimental group was 29 cases. The total sample size needed to be enrolled was 58 cases, and a total of 65 subjects were required according to the 10% shedding rate.

This study was divided into three stages: screening period, treatment period and follow-up period. During treatment, tumor status was assessed by imaging every 6 weeks (±7 days) until disease progression (PD, RECIST 1.1) or death (during patient treatment) or toxicity intolerance or other protocol criteria for discontinuation of study therapy were met. A maximum of 6 treatment cycles of AG chemotherapy were specified, and soantinib was continued until disease progression (PD, RECIST 1.1) or death (during patient treatment) or toxicity intolerance or other criteria for discontinuation of study therapy were met in the protocol. Tumor treatment and survival status after disease progression were recorded. Safety outcomes included AE, changes in laboratory test values, vital signs and electrocardiogram changes.

This is a single-center, open-label randomized controlled Phase II clinical study to observe and evaluate the efficacy and safety of solantinib combined with AG versus AG first-line therapy in patients with locally advanced or metastatic pancreatic cancer.

According to the literature analysis, the mPFS of gemcitabine combined with albumin-bound paclitaxel in first-line treatment of metastatic pancreatic cancer in historical control studies was 3.56 months, and the PFS of solantinib combined with AG regimen was expected to increase from 2.06 months to 4.5 months after 2 cycles of AG regimen. Follow-up time was 12 months and enrollment time was 18 months. α=0.05 and β=0.2 were used for bilateral test, and PASS 22 software was used for analysis. The sample size of AG group in the control group was 29 cases, and that of AG combined with solvatinib in the experimental group was 29 cases. The total sample size required to be enrolled was 58 cases, and a total of 65 subjects were required according to the calculation of 10% shedding rate.

The study was divided into three stages: screening period, treatment period and follow-up period. During treatment, the tumor was evaluated by imaging every 6 weeks (±7 days) until disease progression (PD, RECIST 1.1) or death (during the patient's treatment) or toxicity became intolerable or other protocol criteria for discontinuation of study therapy were met. It is specified that AG chemotherapy should not exceed a maximum of 8 treatment cycles, and that solantinib should be continued until disease progression (PD, RECIST 1.1) or death (in the course of patient treatment) or toxicity becomes intolerable or other criteria for discontinuation of study therapy as specified in the protocol are met. The tumor treatment and survival status after disease progression were recorded. Safety outcome measures included AE, changes in laboratory test values, vital signs and electrocardiogram changes.

Researchers can add unplanned imaging tests for tumors as clinically necessary.

Subjects must meet all of the following criteria for enrollment:

1. The subjects voluntarily joined the study and signed the informed consent with good compliance and follow-up;
2. Unresectable, locally advanced or metastatic pancreatic cancer confirmed by histopathology or cytology;
3. Aged between 18 and 75 (including 18 and 75), male or female;
4. ECOG score: 0-1; Expected survival ≥12 weeks;
5. Patients who had previously received 2 cycles of AG regimen first-line systemic therapy for locally advanced or metastatic pancreatic cancer and whose efficacy was evaluated as CR, PR, SD (excluding SD patients whose efficacy was evaluated as increased after 2 cycles of therapy);
6. Patients with postoperative distant metastasis had received adjuvant chemotherapy of one type and the distance from adjuvant therapy time \&gt; Patients with recurrence at 6 months could be included in the group;
7. At least one measurable lesion (according to RECIST 1.1 criteria); Magnetic resonance imaging (MRI) enhancement or computed tomography (CT) enhancement accurately measured the diameter of ≥10mm, conventional CT scan to determine the diameter of at least 20mm.
8. No serious organic diseases of heart, lung, brain and other organs;
9. The functions of major organs and bone marrow are basically normal:

   1. Blood routine: white blood cells ≥ 4.0 x 109/L, neutrophils ≥ 1.5 x 109/L, platelets ≥ 80 x 109/L, hemoglobin ≥ 90g/L;
   2. International Standardized ratio (INR) and activated partial thrombin time (APTT) ≤1.5× upper limit of normal value (ULN);
   3. Liver function: serum total bilirubin ≤ 1.5 x ULN, ALT/AST ≤ 3 x ULN, serum total biliary red ≤ 1.5 x ULN after internal/external drainage for obstructive jaundice;
   4. Renal function: serum creatinine ≤ 1.5 x ULN, creatinine clearance (CCr) ≥ 50mL/min;
   5. Normal cardiac function, left ventricular ejection fraction (LVEF)≥50% by two-dimensional echocardiography;
10. Fertile male or female patients volunteered to use effective contraceptive methods, such as double screen contraceptives, condoms, oral or injectable contraceptives, intrauterine devices, etc., during the study period and within 6 months of the last study medication. All female patients will be considered fertile unless they have undergone natural menopause, artificial menopause or sterilization.

Those who met each of the above criteria were included in the study.

The study proposal shall be excluded if any of the following criteria are met:

1. Participated in clinical trials of other antitumor drugs within 4 weeks before enrollment;
2. Prior treatment with VEGFR inhibitors or prior treatment with immune checkpoint inhibitors;
3. Patients with BRCA1/2 germ line mutation;
4. Patients with obstructive jaundice but failing to reach the expected yellow reduction;
5. Have had other malignancies within the past 5 years, other than basal cell or squamous cell carcinoma of the skin after radical surgery, or carcinoma in situ of the cervix;
6. Patients who have had or currently have any brain metastases;
7. The investigators determined that liver metastases accounted for 70% or more of the total liver volume;
8. Had received any surgery (except biopsy) or invasive treatment or operation within 4 weeks prior to inclusion, and the surgical incision was not completely healed (except intravenous catheterization, puncture drainage, internal/external drainage for obstructive jaundice, etc.);
9. Uncontrolled pleural effusion, pericardial effusion or ascites requiring drainage;
10. Local antitumor therapy, such as hepatic artery interventional embolization, liver metastasis cryoablation or radiofrequency ablation, was received within 4 weeks before enrollment;
11. Electrolyte abnormalities identified by the investigator as clinically significant;
12. The patient has medically uncontrolled hypertension, as follows: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg;
13. Urine routine indicated urinary protein ≥2+ and 24-hour urinary protein volume \&gt; 1.0g;
14. Patients whose tumors are judged to be at high risk of invading vital blood vessels and causing fatal haemorrhage during the follow-up study;
15. Patients with significant evidence or history of bleeding tendency within 3 months prior to enrollment (bleeding within 3 months \&gt; 30 mL, hematemesis, black feces, blood in stool), hemoptysis (within 4 weeks \&gt; 5 mL fresh blood); A history of hereditary or acquired bleeding or a coagulation disorder. Have clinically significant bleeding symptoms or definite bleeding tendency within 3 months, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, etc.;
16. Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction, severe/unstable angina, or coronary artery bypass grafting within 6 months prior to enrollment; New York Heart Association (NYHA) Grades for Congestive Heart Failure \&gt; Level 2; Ventricular arrhythmias requiring medical treatment; Electrocardiogram (ECG) showed a QT c interval ≥480 ms;
17. Active or uncontrolled severe infection (≥CTCAE grade 2 infection);
18. Unmitigated toxic reactions higher than CTCAE grade 2 or above due to any previous anticancer therapy, excluding grade 2 or less neurotoxicity due to alopecia, lymphocytopenia, and oxaliplatin;
19. Women who are pregnant (positive pregnancy test before medication) or breastfeeding;
20. Any other medical condition, clinically significant metabolic abnormality, physical abnormality or laboratory abnormality, which, in the investigator's judgment, the patient has a medical condition or condition that is reasonably suspected to be unsuitable for the use of the study drug (such as the presence of epileptic seizures requiring treatment), or which would interfere with the interpretation of the study results, or place the patient at high risk;
21. Known human immunodeficiency virus (HIV) infection; A known history of clinically significant liver disease, including viral hepatitis \[active HBV infection must be ruled out as a known carrier of hepatitis B virus (HBV), i.e. positive HBV DNA (\&gt;1×104 copies /mL or \&gt; 2000 IU/ml); known hepatitis C virus infection (HCV) and HCV RNA positive (\&gt;1×103 copies /mL), or other hepatitis, cirrhosis;
22. The presence of any active, known or suspected autoimmune disease (including but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, enteritis, multiple sclerosis, vasculitis, glomerulonephritis, uveitis, pituitaritis, hyperthyroidism, etc.);
23. Allergy or suspected allergy to the study drug or similar drug;
24. In the investigator's judgment, the patient had other factors that might affect the study results or lead to the termination of the study, such as alcoholism, drug abuse, other serious medical conditions (including mental illness) requiring concomitant treatment, serious laboratory abnormalities, and family or social factors that would affect the patient's safety.

Eligibility Criteria:
Inclusion Criteria:

Subjects must meet all of the following criteria for enrollment:

1. The subjects voluntarily joined the study and signed the informed consent with good compliance and follow-up;
2. Unresectable, locally advanced or metastatic pancreatic cancer confirmed by histopathology or cytology;
3. Aged between 18 and 75 (including 18 and 75), male or female;
4. ECOG score: 0-1; Expected survival ≥12 weeks;
5. Patients who had previously received 2 cycles of AG regimen first-line systemic therapy for locally advanced or metastatic pancreatic cancer and whose efficacy was evaluated as CR, PR, SD (excluding SD patients whose efficacy was evaluated as increased after 2 cycles of therapy);
6. Patients with postoperative distant metastasis had received adjuvant chemotherapy of one type and the distance from adjuvant therapy time \&gt; Patients with recurrence at 6 months could be included in the group;
7. At least one measurable lesion (according to RECIST 1.1 criteria); Magnetic resonance imaging (MRI) enhancement or computed tomography (CT) enhancement accurately measured the diameter of ≥10mm, conventional CT scan to determine the diameter of at least 20mm.
8. No serious organic diseases of heart, lung, brain and other organs;
9. The functions of major organs and bone marrow are basically normal:

   1. Blood routine: white blood cells ≥ 4.0 x 109/L, neutrophils ≥ 1.5 x 109/L, platelets ≥ 80 x 109/L, hemoglobin ≥ 90g/L;
   2. International Standardized ratio (INR) and activated partial thrombin time (APTT) ≤1.5× upper limit of normal value (ULN);
   3. Liver function: serum total bilirubin ≤ 1.5 x ULN, ALT/AST ≤ 3 x ULN, serum total biliary red ≤ 1.5 x ULN after internal/external drainage for obstructive jaundice;
   4. Renal function: serum creatinine ≤ 1.5 x ULN, creatinine clearance (CCr) ≥ 50mL/min;
   5. Normal cardiac function, left ventricular ejection fraction (LVEF)≥50% by two-dimensional echocardiography;
10. Fertile male or female patients volunteered to use effective contraceptive methods, such as double screen contraceptives, condoms, oral or injectable contraceptives, intrauterine devices, etc., during the study period and within 6 months of the last study medication. All female patients will be considered fertile unless they have undergone natural menopause, artificial menopause or sterilization.

Those who met each of the above criteria were included in the study.

Exclusion Criteria:

The study proposal shall be excluded if any of the following criteria are met:

1. Participated in clinical trials of other antitumor drugs within 4 weeks before enrollment;
2. Prior treatment with VEGFR inhibitors or prior treatment with immune checkpoint inhibitors;
3. Patients with BRCA1/2 germ line mutation;
4. Patients with obstructive jaundice but failing to reach the expected yellow reduction;
5. Have had other malignancies within the past 5 years, other than basal cell or squamous cell carcinoma of the skin after radical surgery, or carcinoma in situ of the cervix;
6. Patients who have had or currently have any brain metastases;
7. The investigators determined that liver metastases accounted for 70% or more of the total liver volume;
8. Had received any surgery (except biopsy) or invasive treatment or operation within 4 weeks prior to inclusion, and the surgical incision was not completely healed (except intravenous catheterization, puncture drainage, internal/external drainage for obstructive jaundice, etc.);
9. Uncontrolled pleural effusion, pericardial effusion or ascites requiring drainage;
10. Local antitumor therapy, such as hepatic artery interventional embolization, liver metastasis cryoablation or radiofrequency ablation, was received within 4 weeks before enrollment;
11. Electrolyte abnormalities identified by the investigator as clinically significant;
12. The patient has medically uncontrolled hypertension, as follows: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg;
13. Urine routine indicated urinary protein ≥2+ and 24-hour urinary protein volume \&gt; 1.0g;
14. Patients whose tumors are judged to be at high risk of invading vital blood vessels and causing fatal haemorrhage during the follow-up study;
15. Patients with significant evidence or history of bleeding tendency within 3 months prior to enrollment (bleeding within 3 months \&gt; 30 mL, hematemesis, black feces, blood in stool), hemoptysis (within 4 weeks \&gt; 5 mL fresh blood); A history of hereditary or acquired bleeding or a coagulation disorder. Have clinically significant bleeding symptoms or definite bleeding tendency within 3 months, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, etc.;
16. Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction, severe/unstable angina, or coronary artery bypass grafting within 6 months prior to enrollment; New York Heart Association (NYHA) Grades for Congestive Heart Failure \&gt; Level 2; Ventricular arrhythmias requiring medical treatment; Electrocardiogram (ECG) showed a QT c interval ≥480 ms;
17. Active or uncontrolled severe infection (≥CTCAE grade 2 infection);
18. Unmitigated toxic reactions higher than CTCAE grade 2 or above due to any previous anticancer therapy, excluding grade 2 or less neurotoxicity due to alopecia, lymphocytopenia, and oxaliplatin;
19. Women who are pregnant (positive pregnancy test before medication) or breastfeeding;
20. Any other medical condition, clinically significant metabolic abnormality, physical abnormality or laboratory abnormality, which, in the investigator's judgment, the patient has a medical condition or condition that is reasonably suspected to be unsuitable for the use of the study drug (such as the presence of epileptic seizures requiring treatment), or which would interfere with the interpretation of the study results, or place the patient at high risk;
21. Known human immunodeficiency virus (HIV) infection; A known history of clinically significant liver disease, including viral hepatitis \[active HBV infection must be ruled out as a known carrier of hepatitis B virus (HBV), i.e. positive HBV DNA (\&gt;1×104 copies /mL or \&gt; 2000 IU/ml); known hepatitis C virus infection (HCV) and HCV RNA positive (\&gt;1×103 copies /mL), or other hepatitis, cirrhosis;
22. The presence of any active, known or suspected autoimmune disease (including but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, enteritis, multiple sclerosis, vasculitis, glomerulonephritis, uveitis, pituitaritis, hyperthyroidism, etc.);
23. Allergy or suspected allergy to the study drug or similar drug;
24. In the investigator's judgment, the patient had other factors that might affect the study results or lead to the termination of the study, such as alcoholism, drug abuse, other serious medical conditions (including mental illness) requiring concomitant treatment, serious laboratory abnormalities, and family or social factors that would affect the patient's safety.