Neo-Sequence 1: Neoadjuvant Chemotherapy With or Without Antiangiogenesis and Sequential Immunotherapy for HER2-negative MMR-proficient Locally Advanced Gastric or Gastroesophageal Adenocarcinoma

Neo-Sequence 1: Phase 2 Study of Neoadjuvant Chemotherapy With or Without Antiangiogenesis and Sequential Immunotherapy for HER2-negative MMR-proficient Locally Advanced Gastric or Gastroesophageal Adenocarcinoma

This is a single-institution, prospective phase II trial designed to evaluate the efficacy of neoadjuvant chemotherapy and sequential immunotherapy in patients with locally advanced esophagogastric junction and gastric adenocarcinoma. Patients with Her-2 positive or dMMR tumors will be excluded from the study. Six cycles of nab-paclitaxel, oxaliplatin and S-1 with or without bevacizumab, followed by three circles of nab-paclitaxel, bevacizumab, with or without S-1 combined with two cycles of PD-1 monoclonal antibody, will be administered as neoadjuvant therapy. Patients will receive different adjuvant treatments depending on the degrees of surgical radicality and the pathological reactions of tumors.

Study Overview

• Status: Completed
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: SOX plus Paclitaxel with or without antiangiogenesis followed by PD-1 antibody

Detailed Description

The regimen of neoadjuvant chemotherapy is nab-paclitaxel (130mg/m2 of BSA, intravenously day 1), oxaliplatin (70mg/m2 of BSA, intravenously day 1) and S-1 (40~60 mg orally twice a day, days 1-8), which will be administered biweekly for six cycles. A comprehensive evaluation, including chest, abdominal and pelvic CT, ultrasonography of cervical lymph nodes and supraclavicular lymph nodes, endoscopy and endoscopic ultrasound, will be performed every 3 cycles. If patients respond to chemotherapy, then they will receive 2 cycles of PD-1 antibody every 3 weeks. Surgery will be performed approximately 8-12 weeks after the last dosage of PD-1 antibody. Postoperatively, immunotherapy or chemotherapy will be administered as adjuvant therapy depending on the degrees of surgical radicality and the pathological reactions of tumors. For patients who have no response to neoadjuvant chemotherapy, surgery, radiation or another systemic regimen will be optioned.

• Study Type: Observational
• Enrollment (Actual): 70

Contacts and Locations

• Study Contact: Name: Chunxia Du, M.D.; Phone Number: +86-010-87788130; Email: retinadcx@vip.163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100021
      • National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with endoscopically biopsy-proven Her-2(-), pMMR gastric cancer will receive preoperative neoadjuvant therapy.

Description

Inclusion Criteria:

1. Be willing and able to provide written (signed) informed consent;
2. Age ≥ 18 years and ≤75 years.
3. Has a pathologic diagnosis of gastroesophageal or gastric adenocarcinoma, mucinous adenocarcinoma or signet ring cell carcinoma.
4. Imaging (CT/ultrasonography of cervical lymph nodes and supraclavicular lymph nodes/ endoscopy and endoscopic ultrasound) confirmed at the stage of cT3/4a NanyM0(AJCC 8th).

5. Confirmed by immunohistochemistry (IHC) staining or genetic and transcriptional profiling detection to meet all of the following conditions:

   1. Her-2-negative was defined as IHC -, IHC 1+ or IHC 2+ and FISH negative;
   2. Mismatch repair-proficient (pMMR).
6. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1;

7. The main organ function meets the following criteria within 7 days before treatment:

   1. Hemoglobin (Hb) level ≥9.0 g/dl.
   2. Neutrophil count (ANC)≥1.5×10^9/L.
   3. Platelet (PLT) ≥100×10^9/L
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤2.5×ULN.
   5. Serum creatinine (Cr) level ≤1.0×ULN and creatinine clearance ≥60 ml/min.
   6. Total bilirubin(TBIL) level ≤1.5×ULN.

Exclusion Criteria:

1. Confirmed at stage IV (AJCC 8th) or unresectable by investigator before enrolling.
2. Patienta have had prior chemotherapy, targeted small molecule therapy, or radiation therapy for the current diagnosis of EGJ cancer or gastric cancer.
3. Patients are allergic to study medication and its ingredients.
4. Patients have experienced or currently have other malignancies within 5 years.
5. Patients have an active infection requiring systemic therapy.
6. Women who are pregnant, breast-feeding or planning to become pregnant during treatment or within 6 months after treatment ends.
7. Patients have a history of psychotropic substance abuse and are unable to quit or have a mental disorder.
8. Patients with other severe acute or chronic conditions that may increase the risk of participation in the study and study treatment, or may interfere with interpretation of study results, and judged by the investigator as not suitable for participation in this clinical trial.
9. Diagnosis of immunodeficiency or active autoimmune disease, receiving or being treated with immunomodulators, systemic steroids or immunosuppressive drugs in the past two years.
10. Patients with gastrointestinal obstruction or uncontrolled bleeding undergo emergency surgery.
11. The proportion of other components in the pathology (such as squamous cell carcinoma, neuroendocrine carcinoma, etc.) exceeds 10%

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

SOX plus Paclitaxel with or without antiangiogenesis followed by PD-1 antibody; SOX: Oxaliplatin+S-1

Drug: SOX plus Paclitaxel with or without antiangiogenesis followed by PD-1 antibody; Drug: Paclitaxel(albumin-bound) 130mg/m2, ivgtt, D1, Q2w Drug: Oxaliplatin 70 mg/m2, ivgtt, D1, q2w Drug: S-1 40mg (body surface area < 1.25m2), bid, D1-8, Q2w 50mg (body surface area >1.25m2, <1.5 m2), bid, D1-8, Q2w 60mg (body surface area >1.5m2), bid, D1-8, Q2w Drug: Bevacizumab, 5mg/kg, ivgtt, D1, Q14d Drug: PD-1 antibody, 200mg, ivgtt, D1, Q21d Patients with Her-2 negative, MMR-proficient locally advanced esophagogastric junction or gastric adenocarcinoma will receive 6 cycles of neoadjuvant chemotherapy with or without antiangiogenesis. After comprehensive evaluations, patients who respond to chemotherapy will further receive 2 cycles of PD-1 antibody comibed with antiangiogenesis and chemotherapy as neoadjuvant therapy. Drug: Pembrolizumab or sintilimab, 100~200mg, ivgtt, D1, Q3w. Patients will make the final decision of PD -1 antibody according to their economic condition.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	The time from recruitment to any progression of disease precluding surgery, progression or recurrence of disease after surgery, progression of disease in the absence of surgery, or death from any cause.	From the recruitment to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major pathological response	It is defined as residual tumors less than 10% after neoadjuvant systemic therapy according to Mandard grade.	From the date of recruitment to 3 months after all treatment ends
Overall survival(OS)	The time from recruitment to the date of death for any reason or the date of last follow-up	From the date of recruitment to the date of death from any cause or the date of last follow-up, assessed up to 36 months
R0 resection rate	Rate of microscopically margin-negative resection	From the date of recruitment to 3 months after all treatment ends
Adverse events	Adverse events (AEs) of neoadjuvant and adjuvant systemic therapy will be graded and documented according to NCI-CTCAE v5.0 and immune-related Adverse Event, irAE from the beginning of treatment to 3 months since the last dosage of treatment. Documentary will include severity, lasting period and occurrence time. Surgery complications will also be documented.	From the date of recruitment to 3 months after all treatment ends

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: September 12, 2022
• First Submitted That Met QC Criteria: September 12, 2022
• First Posted (Actual): September 14, 2022

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 14, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: safety; Efficacy; Immunotherapy; Neoadjuvant Chemotherapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Antibodies
• Other Study ID Numbers: 21/489-3160

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No