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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
41
In phase Ib, surufatinib will be orally administrated 200 mg once a day (QD) or 250 mg QD per cohort escalation assignment on a 21-day cycle. In phase II, surufatinib will be orally administrated at RP2D as determined in phase Ib.
Nab-paclitaxel will be administrated at 125 mg/m2 intravenously on day 1 and 8 of each 21-day cycle.
Gemcitabine will be administrated at 1000 mg/m2 intravenously on day 1 and 8 of each 21-day cycle.
Nab-paclitaxel will be administrated at 125 mg/m2 intravenously on day 1 and 8 of each 21-day cycle.
Zhongshan Hospital
Shanghai, Shanghai Municipality, China
RECRUITINGObjective response rate (RECIST 1.1)
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.
Time frame: 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
Objective response rate (irRECIST)
It will be evaluated based on the immune-related (ir) RECIST criteria.
Time frame: 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
DCR is defined as the percentage of patients who achieved CR, PR and stable disease (SD), and will be evaluated based on RECIST 1.1 and the irRECIST criteria.
Time frame: 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)
DoR is defined as the time from first documented objective response (CR or PR, whichever occurs first, as per RECIST v1.1) to disease progression or death, whichever occurs first.
Time frame: 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
Progression free survival (RECIST 1.1)
PFS is defined as the time from the date of first dose of study drugs to the date of the first documented disease progression (determined as per RECIST v1.1) or date of death, whichever occurs first.
Time frame: 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
Time frame: From date of first dose until the date of death from any cause, assessed up to 24 months
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 CTCAE Version 5.0. Dose-limiting toxicities (DLT) will be evaluated by the investigators 28 days after the first dose of study drugs in order to determine the RP2D of surufatinib in combination with KN046 and the AG regimen in phase Ib.
Time frame: From first dose to within 90 days after the last dose, up to 24 months
Predictive biomarkers
To evaluate the correlation between potential biomarkers and the prognosis of patients treated with this regimen. Tumor tissue or blood samples will be examined to assess relevant parameters including MSI/dMMR status, TMB, PD-1/PD-L1/CTLA-4 expression, VEGFR/FGFR/CSF-1R expression, plasma ctDNA, tumor markers such as CA19-9/CEA before and after treatment, plasma concentration of sVEGFR2, VEGF, FGF23, FGF2, M-CSF, etc.
Time frame: From date of screening until the date of death, assessed up to 24 months
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