Neoadjuvant Nab-Paclitaxel Plus Oxaliplatin, S-1, and Sintilimab in Early-Onset Resectable Gastric Cancer

Official title

Efficacy and Safety of Neoadjuvant Nab-Paclitaxel Combined With Oxaliplatin, S-1, and Sintilimab in Patients With Locally Advanced Resectable Early-onset Gastric Cancer: A Phase II, Single-Arm, Open-Label Clinical Trial

Overview

This study aims to evaluate the effectiveness and safety of a preoperative treatment (called neoadjuvant therapy) combining four drugs-nab-paclitaxel, oxaliplatin, S-1, and sintilimab-for patients with locally advanced, resectable early-onset gastric cancer (diagnosed at age 45 or younger). All participants will receive this drug combination before undergoing surgery to remove the tumor. The goal is to shrink the tumor, increase the chance of complete surgical removal, and improve long-term outcomes. This is a single-arm, open-label, phase II clinical trial, meaning all participants will receive the same treatment, and both doctors and patients will know what drugs are being used. The study is being conducted at Peking University People's Hospital.

Interventions

• Drug nab-paclitaxel
  Nab-paclitaxel is administered as an intravenous (IV) infusion at a dose of 125 mg/m² on day 1 of each 3-week cycle, for a total of 3 cycles in the neoadjuvant (preoperative) setting.
• Drug oxaliplatin
  Oxaliplatin is administered as an intravenous (IV) infusion at a dose of 85 mg/m² on day 1 of each 3-week cycle, for a total of 3 cycles in the neoadjuvant (preoperative) setting.
• Drug S-1
  S-1 is administered orally twice daily (BID) on days 2 to 15 of each 3-week cycle, for a total of 3 cycles. The dose is based on body surface area (BSA) as follows: BSA \< 1.25 m²: 40 mg BID (total 80 mg/day); BSA 1.25-1.5 m²: 50 mg BID (total 100 mg/day); BSA \> 1.5 m²: 60 mg BID (total 120 mg/day)
• Drug sintilimab
  Sintilimab is administered as an intravenous (IV) infusion at a fixed dose of 200 mg on day 1 of each 3-week cycle, for a total of 3 cycles in the neoadjuvant (preoperative) setting.
• Procedure D2 Gastrectomy
  Curative-intent D2 radical gastrectomy is performed 3 to 6 weeks after completion of neoadjuvant therapy. The procedure includes either proximal, distal or total gastrectomy depending on tumor location, with en bloc resection of the stomach and systematic D2 lymphadenectomy according to Japanese Gastric Cancer Association (JGCA) guidelines. D2 lymph node dissection involves removal of both perigastric (N1) and second-tier (N2) lymph nodes.

Primary outcome measures

• Pathological complete response (pCR) rate after neoadjuvant therapy [Time frame: At the time of surgery, approximately 13-16 weeks from the start of neoadjuvant therapy]

Secondary outcome measures (6)

• R0 resection rate after neoadjuvant therapy and surgery [Time frame: At the time of surgery, approximately 13-16 weeks from the start of treatment]
• Major pathological response (MPR) rate based on Becker tumor regression grade [Time frame: At the time of surgery, approximately 13-16 weeks from the start of treatment]
• 3-year disease-free survival (DFS) [Time frame: Up to 36 months after surgery]
• 3-year overall survival (OS) [Time frame: Up to 36 months after surgery]
• Incidence of treatment-related grade 3 or higher adverse events [Time frame: From initiation of treatment to surgery, approximately 12-15 weeks]
• Incidence of major postoperative complications [Time frame: From surgery until hospital discharge or 30 days postoperatively, whichever is longer]

Eligibility criteria

Inclusion criteria

• Participants must meet all of the following inclusion criteria:
• Male or female, aged ≥16 and ≤45 years;
• Karnofsky performance score ≥70% or ECOG performance status 0-1;
• Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction (GEJ).
• For gastric body cancer: clinical stage cT3-T4a N+ M0;
• For GEJ cancer: clinical stage cT2-T4a N+ M0;
• For cT4b Nany M0 cases: location may be gastric body or GEJ.
• Staging is based on contrast-enhanced CT, MRI (if needed), and endoscopic ultrasonography (EUS) (if needed);
• Assessed as resectable after multidisciplinary team (MDT) discussion;
• Surgical evaluation confirms that D2 radical gastrectomy is feasible;
• Sufficient physical condition and organ function to tolerate major abdominal surgery;
• Baseline laboratory tests meet the following criteria:
• Hemoglobin ≥90 g/L
• Absolute neutrophil count (ANC) ≥1.5×10⁹/L
• Platelets ≥100×10⁹/L
• ALT and AST ≤2.5× upper limit of normal (ULN)
• Alkaline phosphatase (ALP) ≤2.5× ULN
• Total bilirubin <1.5× ULN
• Serum creatinine <1× ULN
• Serum albumin ≥30 g/L
• No severe comorbidities that may limit life expectancy to <3 years;
• Participant is willing and able to comply with the study protocol during the study period;
• Written informed consent must be signed before screening. Participants must understand their right to withdraw at any time without any loss of benefits;
• Willing to provide blood and tissue samples.

Exclusion criteria

• Participants meeting any of the following criteria will be excluded:
• Patients with HER-2 positive gastric cancer, as determined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH);
• Patients with dMMR (deficient mismatch repair) or MSI-H (microsatellite instability-high) tumors, as determined by IHC;
• Pregnant or breastfeeding women;
• Prior treatment for gastric cancer with cytotoxic chemotherapy, radiotherapy, or immunotherapy;
• History of other malignancies within the past 5 years;
• Active autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis;
• Active inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis;
• Currently receiving systemic corticosteroids or other immunosuppressive therapy;
• Prior organ transplantation or use of anti-rejection medications;
• Active tuberculosis, HIV infection, or severe active hepatitis B or C;
• History of uncontrolled epilepsy, central nervous system disorders, or psychiatric illnesses that, in the investigator's judgment, may interfere with informed consent or compliance with oral medication;
• Clinically significant (active) cardiac diseases, including symptomatic coronary artery disease, NYHA class II or above congestive heart failure , severe arrhythmias requiring medical intervention, or myocardial infarction within the past 12 months;
• Presence of upper gastrointestinal obstruction that may impair the oral intake or absorption of S-1;
• Severe uncontrolled recurrent infections or other uncontrolled serious comorbidities;
• Use of any investigational drugs within 4 weeks prior to study enrollment.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University People's Hospital — Beijing

Publications

• Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. doi: 10.1097/01.sla.0000133083.54934.ae. PMID 15273542
• Becker K, Mueller JD, Schulmacher C, Ott K, Fink U, Busch R, Bottcher K, Siewert JR, Hofler H. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 2003 Oct 1;98(7):1521-30. doi: 10.1002/cncr.11660. PMID 14508841
• Watson S, de la Fouchardiere C, Kim S, Cohen R, Bachet JB, Tournigand C, Ferraz JM, Lefevre M, Colin D, Svrcek M, Meurisse A, Louvet C. Oxaliplatin, 5-Fluorouracil and Nab-paclitaxel as perioperative regimen in patients with resectable gastric adenocarcinoma: A GERCOR phase II study (FOXAGAST). Eur J Cancer. 2019 Jan;107:46-52. doi: 10.1016/j.ejca.2018.11.006. Epub 2018 Dec 7. PMID 30529902
• Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. Lancet PMID 28404157
• Zhang C, Tang R, Zhu H, Ge X, Wang Y, Wang X, Miao L. Comparison of treatment strategies and survival of early-onset gastric cancer: a population-based study. Sci Rep. 2022 Apr 15;12(1):6288. doi: 10.1038/s41598-022-10156-5. PMID 35428811
• Liu L, Lin J, Zhao J, Yan P. Analysis of clinicopathologic characteristics and prognosis of gastric cancer in patients <40 years. Medicine (Baltimore). 2023 Aug 25;102(34):e34635. doi: 10.1097/MD.0000000000034635. PMID 37653814
• Liu JD, Ye BT, Fu M, Zhang Q, Chen H, Sun J, Cai TY, Wang ZM, He HY, Zhao JJ, Li HJ, Wang XF, Sun YH. [Clinicopathological and molecular diagnostic features of early-onset gastric cancer: a study based on data from a single-center dedicated gastric cancer database]. Zhonghua Wei Chang Wai Ke Za Zhi. 2023 Oct 25;26(10):963-967. doi: 10.3760/cma.j.cn441530-20230603-00190. Chinese. PMID 37849267
• Pocurull A, Herrera-Pariente C, Carballal S, Llach J, Sanchez A, Carot L, Botargues JM, Cuatrecasas M, Ocana T, Balaguer F, Bujanda L, Moreira L. Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study. Cancers (Basel). 2021 Jun 23;13(13):3132. doi: 10.3390/cancers13133132. PMID 34201547

Identifiers

NCT: NCT07018063 · PKUPH-EOGC-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗