1475TiP - Fruquintinib in combination with sintilimab and CAPEOX as first-line treatment for advanced G/GEJ cancer: A phase Ib/II clinical trial (FUNCTION)

Background

Gastric and gastroesophageal junction (G/GEJ) cancer is one of the most common malignancies and the fourth leading cause of cancer related death globally. Fruquintinib is a highly selective oral tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. The phase 3 study FRUTIGA demonstrated fruquintinib plus paclitaxel was superior to paclitaxel alone in improving outcomes in patients with G/GEJ cancer. As anti-angiogenesis can enhance the efficacy of immunotherapy, we designed this study to evaluate the safety and efficacy of fruquintinib plus sintilimab, an NMPA-approved PD-1 inhibitor, and CAPEOX as first-line treatment for advanced G/GEJ cancer.

Trial design

This is a multicenter, single-arm, open-label, phase 1b/2 study conducted in China. The phase 1b study will adopt a 3+3 design with escalating oral daily dose of 3 to 5 mg (1 mg per level) fruquintinib for days 1-14 in combination with sintilimab 200 mg intravenously once for day 1, capecitabine 800mg/m² orally twice a day for days 1-14, and oxaliplatin 130mg/m² intravenously once for day 1 using a 21-day cycle. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of fruquintinib will be determined in the phase 1b study with a dose-limiting toxicity (DLT) period of the first cycle. Major DLTs are defined as any of the following toxicities occurring in the DLT period determined to be related to study treatment: grade ≥ 4 hematological toxicities, grade ≥ 3 non-hematological toxicities, and toxicities that required discontinuation of fruquintinib or sintilimab ≥ 21 days. 3 to 9 systematic treatment-naïve patients with advanced G/GEJ cancer are expected to be enrolled in the phase 1b study, depending on observed DLTs and the need for dose adjustments. In the phase 2 study, 61 additional patients will be enrolled with RP2D administered. Upon chemotherapy cycles completed, fruquintinib plus sintilimab will be administered as maintenance treatment. The treatment continues until progressive disease or intolerable toxicity. The primary endpoint of the phase 2 study is ORR. The secondary endpoints include OS, PFS, DCR, DoR, surgical conversion rate, safety, and molecular biomarker.

Clinical trial identification

NCT06329973.

Editorial acknowledgement

Chao Zhao, Zheng Wang, and Yong Ma from Hutchmed for the assistance in writing.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.