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Gastrointestinal Diseases

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Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

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Antimetabolites

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.

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.

surufatinib

Nab-paclitaxel will be administrated at 125 mg/m2 intravenously on day 1 and 8 of each 21-day cycle.

KN046

Gemcitabine will be administrated at 1000 mg/m2 intravenously on day 1 and 8 of each 21-day cycle.

gemcitabine

Nab paclitaxel

Wen-Quan Wang, MD, PhD

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.

Surufatinib Combined With KN046 and AG Regimen Chemotherapy as First-Line Treatment for Unresectable Advanced Pancreatic Cancer

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

The IPD will not be shared with other researchers in order to protect patients' privacy.

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.

It will be evaluated based on the immune-related (ir) RECIST criteria.

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.

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.

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.

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.

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.

Spots Global Cancer Trial Database for unresectable locally advanced or metastatic pancreatic cancer