A Phase Ib/II Clinical Trial to Evaluate the Efficacy and Safety of Surufatinib in Combination With KN046 and AG Regimen Chemotherapy for the First-Line Treatment of Unresectable Advanced Pancreatic Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 41
- 试验地点
- 1
- 主要终点
- Objective response rate (RECIST 1.1)
研究概览
简要总结
Advanced pancreatic cancer is a highly aggressive and fatal disease with an extremely low 5-year survival rate. Combined chemotherapy is the mainstay of treatment for patients with unresectable advanced pancreatic cancer, and the combination of nab-paclitaxel and gemcitabine (AG regimen) has been one of the most commonly used regimens for more than a decade. However, chemo-resistance often occurs within half a year and the efficacy remains unsatisfied with an overall survival of only 9~11 months.
Immune checkpoint inhibitors (ICIs) such as anti-PD-1/L1 antibody and anti-CTLA-4 antibody have demonstrated encouraging anti-tumor efficacy in multiple solid tumors including lung cancer, gastric cancer, and esophageal cancer, while obtained controversial results when combined with chemotherapy in pancreatic cancer. Recently, the immune-suppression tumor microenvironment (TME) of pancreatic cancer has been described in several pre-clinical studies, which may explain the resistance against ICIs and chemotherapy.
KN046 is a recombinant humanized PD-L1/CTLA-4 bispecific antibody with innovative designs include a proprietary CTLA-4 domain antibody with a significantly improved safety profile, a bispecific antibody fused with PD-L1 antibody targeting the TME with high PD-L1 expression. Recent clinical studies have shown promising anti-tumor activity of KN046 in pancreatic cancer.
Surufatinib, also known as HMPL-012 or Sulfatinib, is a small molecular tyrosine kinase inhibitor (TKI) targeting the Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor (FGFR) and Colony Stimulating Factor-1 Receptor (CSF-1R), which has a dual mechanism of action of anti-angiogenesis and regulation of immune microenvironment. Previous studies have suggested synergic effect of surufatinib in combination with anti-PD-1 antibodies.
This phase Ib/II clinical trial is intended to investigate the activity and safety of the combination of surufatinib combined with KN046 and the AG regimen chemotherapy as first-line treatment in patients with unresectable locally advanced or metastatic pancreatic cancer.
详细描述
Advanced pancreatic cancer is a highly aggressive and fatal disease with an extremely low 5-year survival rate. Combined chemotherapy is the mainstay of treatment for patients with unresectable advanced pancreatic cancer, and the combination of nab-paclitaxel and gemcitabine (AG regimen) has been one of the most commonly used regimens for more than a decade. However, chemo-resistance often occurs within half a year and the efficacy remains unsatisfied with an overall survival of only 9~11 months.
Immune checkpoint inhibitors (ICIs) such as anti-PD-1/L1 antibody and anti-CTLA-4 antibody have demonstrated encouraging anti-tumor efficacy in multiple solid tumors including lung cancer, gastric cancer, and esophageal cancer, while obtained controversial results when combined with chemotherapy in pancreatic cancer. Recently, the immune-suppression tumor microenvironment (TME) of pancreatic cancer has been described in several pre-clinical studies, which may explain the resistance against ICIs and chemotherapy.
KN046 is a recombinant humanized PD-L1/CTLA-4 bispecific antibody with innovative designs include a proprietary CTLA-4 domain antibody with a significantly improved safety profile, a bispecific antibody fused with PD-L1 antibody targeting the TME with high PD-L1 expression. Recent clinical studies have shown promising anti-tumor activity of KN046 in pancreatic cancer.
Surufatinib, also known as HMPL-012 or Sulfatinib, is a small molecular tyrosine kinase inhibitor (TKI) targeting the Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor (FGFR) and Colony Stimulating Factor-1 Receptor (CSF-1R), which has a dual mechanism of action of anti-angiogenesis and regulation of immune microenvironment. Previous studies have suggested synergic effect of surufatinib in combination with anti-PD-1 antibodies.
This phase Ib/II clinical trial is intended to investigate the activity and safety of the combination of surufatinib combined with KN046 and the AG regimen chemotherapy as first-line treatment in patients with unresectable locally advanced or metastatic pancreatic cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed content obtained prior to treatment.
- •Male or female, age ≥ 18 years and ≤ 75 years.
- •Patients must have histologically or cytologically confirmed pancreatic adenocarcinoma that originated from the pancreatic ductal epithelial, with image-documented unresectable locally advanced or distant metastatic disease.
- •Patients have received no previous local treatment such as surgery, radiotherapy, ablation, or any systemic treatment for advanced/metastatic pancreatic cancer, including neoadjuvant and/or adjuvant therapy.
- •Have at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Expected overall survival of ≥ 6 months.
- •Laboratory test results within 7 days prior to first dose of study drugs must meet the following criteria:
- •absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count (PLT) ≥ 100 × 109/L and hemoglobin (HGB) ≥ 90 g/L.
- •total bilirubin (TBil) ≤ 1.5 × the upper limit of normal (ULN).
- •alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN in the absence of liver metastases; ALT and AST ≤ 3 × ULN in the presence of liver metastases.
- •serum creatinine (SCr) ≤ 1.5 × ULN and creatinine clearance (CCl) ≥ 50 mL/min (calculated according to the Cockcroft-Gault formula).
- •urine protein <2+ in urine analysis; if urine protein ≥2+, 24-hour urine protein quantification should be <1g.
- •international normalized ratio (INR) ≤ 1.5 and partial activation prothrombin time (APTT) ≤ 1.5 × ULN.
- •Female subjects of childbearing age or male subjects whose partner is a female of childbearing age should use effective contraception from at least 1 month prior to the first dose of study drugs to 6 months after the last dose of study drugs.
排除标准
- •Adverse events (AEs) due to previous anti-tumor therapy have not recovered to CTCAE Grade ≤1 (except for hair loss, skin pigment changes, or Grade ≤ 2 neurotoxicity).
- •Other malignancies diagnosed within past 5 years (except basal cell carcinoma of the skin or squamous cell carcinoma and carcinoma in situ of the cervix that have been effectively controlled).
- •Presence of central nervous system (CNS) metastases at screening, or have a history of CNS metastases.
- •Patients who have received approved systemic anti-tumor therapy within 4 weeks before the first dose of study drugs, including chemotherapy, biological therapy, targeted therapy, hormone therapy, traditional Chinese medicine therapy (with clear anti-tumor indications in the label), etc.
- •Patients who have received radical radiotherapy (including radiotherapy involving > 25% bone marrow) within 4 weeks prior to the first study drugs reception; Or brachytherapy (e.g., implanted radioparticles) within 60 days prior to the first dose of the study drugs; Or palliative radiotherapy for bone metastases within 1 week prior to first dose of the study drugs.
- •Patients who have undergone major surgery within 4 weeks before receiving first dose of study drugs, or have unhealed wounds, ulcers or fractures.
- •Vaccination within 4 weeks before the first dose of study drugs or plan to have during the study period, except for inactivated vaccines.
- •Patients who have previously received anti-VEGF/VEGFR agents and have experienced disease progression during treatment or within 3 months after the last dose.
- •Patients with uncontrollable malignant pleural effusion, ascites, or pericardial effusion (no response to diuretics or puncture as per the investigator's judgement).
- •Presence of gastrointestinal diseases such as active gastric and duodenal ulcers, ulcerative colitis, or active bleeding in unresected tumors, or other conditions that may cause gastrointestinal bleeding or perforation as determined by the investigator.
- •Patients with evidence or history of thrombosis or significant bleeding tendency (bleeding >30 mL within 2 months, hematemesis, melena, hematochezia, or hemoptysis >5mL within 4 weeks) within 2 months prior to the first dose of the study drugs.
- •Patients who have arterial thrombosis or deep vein thrombosis within 6 months, or have thromboembolic events (including stroke and/or transient ischaemic attack) within 12 months prior to first dose of the study drugs.
- •Patients who are receiving anti-tuberculosis therapy for active pulmonary tuberculosis, or have had anti-tuberculosis therapy within 1 year prior to first dose of the study drugs.
- •Patients with a previous or current history of pulmonary disorder that may interfere the identification and management of suspected drug-related pulmonary toxicity, including pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe impairment of lung function, etc. (radiation pneumonia in radiotherapy areas is allowed).
- •Presence of corneal lesions, including but not limited to bullous keratopathy, shingle corneal degeneration, corneal abrasions, corneal ulcers, keratitis, etc.
- •History of clinically significant hepatic disease, including, but not limited to, known hepatitis B virus (HBV) infection with HBV DNA positive; known Hepatitis C virus (HCV) infection with HCV RNA positive; or other hepatitis, liver cirrhosis, etc.
- •Positive for human immunodeficiency virus (HIV) antibodies.
- •Meet any of the following criteria for cardiac function:
- •Clinically significant arrhythmias or conduction abnormalities requiring clinical intervention.
- •Electrocardiogram (ECG) indicating an QT interval (QTcF) of > 480 msec.
- •Clinically significant cardiovascular diseases, including acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris, coronary artery bypass grafting, congestive heart failure according to the New York Heart Association (NYHA) classification III/IV, ventricular arrhythmias needing drug intervention, LVEF <50%.
- •Previous or current autoimmune diseases, including but not limited to Crohn's disease, ulcerative colitis, systemic lupus erythematosus, sarcoidosis, Wegener syndrome, Graves' disease, rheumatoid arthritis, pituitary inflammation, ocular pigmentitis, autoimmune hepatitis, systemic sclerosis, Hashimoto's thyroiditis, autoimmune vasculitis, autoimmune neuropathy (Guillain-Barre syndrome), with exceptions as follows: type I diabetes, hormone replacement therapy-stabilized hypothyroidism, psoriasis or vitiligo that does not require systemic therapy.
- •Women who are pregnant or lactating.
- •Known history of allergy to the relevant ingredients of the study drugs.
- •Subjects who have received investigational treatments in other clinical studies within 4 weeks prior to first dose of study drugs.
- •Patients who have any disorder or condition that may affect absorption of the study drugs, or who are unable to take oral medication.
- •Patients unsuitable for participating due to other reasons as per investigator's determination.
研究组 & 干预措施
surufatinib + KN046 + nab-paclitaxel + gemcitabine
In the phase Ib of dose escalation, all patients enrolled will receive: nab-paclitaxel at 125 mg/m2 on days 1 and 8, gemcitabine at 1000 mg/m2 on days 1 and 8, KN046 at 5 mg /kg on day 1, plus surufatinib per cohort escalation assignment starting with 200 mg. The combination treatment repeats every 3 weeks, until disease progression, death, intolerable toxicity, or withdrawal of informed consent. Dose-limiting toxicity will be evaluated 28 days after first dose to determine the recommended phase 2 dose (RP2D) of surufatinib.
Patients enrolled in the phase II of dose expansion will receive the combination regimen of nab-paclitaxel plus gemcitabine plus KN046 plus surufatinib as determined in the phase Ib.
干预措施: surufatinib (Drug)
surufatinib + KN046 + nab-paclitaxel + gemcitabine
In the phase Ib of dose escalation, all patients enrolled will receive: nab-paclitaxel at 125 mg/m2 on days 1 and 8, gemcitabine at 1000 mg/m2 on days 1 and 8, KN046 at 5 mg /kg on day 1, plus surufatinib per cohort escalation assignment starting with 200 mg. The combination treatment repeats every 3 weeks, until disease progression, death, intolerable toxicity, or withdrawal of informed consent. Dose-limiting toxicity will be evaluated 28 days after first dose to determine the recommended phase 2 dose (RP2D) of surufatinib.
Patients enrolled in the phase II of dose expansion will receive the combination regimen of nab-paclitaxel plus gemcitabine plus KN046 plus surufatinib as determined in the phase Ib.
干预措施: KN046 (Drug)
surufatinib + KN046 + nab-paclitaxel + gemcitabine
In the phase Ib of dose escalation, all patients enrolled will receive: nab-paclitaxel at 125 mg/m2 on days 1 and 8, gemcitabine at 1000 mg/m2 on days 1 and 8, KN046 at 5 mg /kg on day 1, plus surufatinib per cohort escalation assignment starting with 200 mg. The combination treatment repeats every 3 weeks, until disease progression, death, intolerable toxicity, or withdrawal of informed consent. Dose-limiting toxicity will be evaluated 28 days after first dose to determine the recommended phase 2 dose (RP2D) of surufatinib.
Patients enrolled in the phase II of dose expansion will receive the combination regimen of nab-paclitaxel plus gemcitabine plus KN046 plus surufatinib as determined in the phase Ib.
干预措施: gemcitabine (Drug)
surufatinib + KN046 + nab-paclitaxel + gemcitabine
In the phase Ib of dose escalation, all patients enrolled will receive: nab-paclitaxel at 125 mg/m2 on days 1 and 8, gemcitabine at 1000 mg/m2 on days 1 and 8, KN046 at 5 mg /kg on day 1, plus surufatinib per cohort escalation assignment starting with 200 mg. The combination treatment repeats every 3 weeks, until disease progression, death, intolerable toxicity, or withdrawal of informed consent. Dose-limiting toxicity will be evaluated 28 days after first dose to determine the recommended phase 2 dose (RP2D) of surufatinib.
Patients enrolled in the phase II of dose expansion will receive the combination regimen of nab-paclitaxel plus gemcitabine plus KN046 plus surufatinib as determined in the phase Ib.
干预措施: Nab paclitaxel (Drug)
结局指标
主要结局
Objective response rate (RECIST 1.1)
时间窗: From date of first dose until the date of first documented progression or date of death from any cause, whichever occurs first, assessed up to 24 months
ORR is defined as the percentage of patients who achieve complete response (CR) or partial response (PR) based on the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
次要结局
- Progression free survival (RECIST 1.1)(From date of first dose until the date of first documented progression or date of death from any cause, whichever occurs first, assessed up to 24 months)
- Safety and tolerability by incidence, severity and outcome of adverse events(From first dose to within 90 days after the last dose, up to 24 months)
- Objective response rate (irRECIST)(From date of first dose until the date of first documented progression or date of death from any cause, whichever occurs first, assessed up to 24 months)
- Disease control rate(From date of first dose until the date of first documented progression or date of death from any cause, whichever occurs first, assessed up to 24 months)
- Duration of response (RECIST 1.1)(From date of first dose until the date of first documented progression or date of death from any cause, whichever occurs first, assessed up to 24 months)
- Overall survival(From date of first dose until the date of death from any cause, assessed up to 24 months)
- Predictive biomarkers(From date of screening until the date of death, assessed up to 24 months)