Radiotherapy + Chemoimmunotherapy Followed by Surgery in Patients With Limited Metastatic Gastric or GEJ Cancer

NCT06121700 | Recruiting Phase 2

• 1 other identifier: FDRT-2022-260-2977
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to evaluate the efficacy and safety of radiotherapy combined with chemotherapy and anti-PD-1 immunotherapy followed by surgery for the primary and metastatic lesions in patients with limited metastatic gastric or gastroesophageal junction adenocarcinoma. The main questions it aims to answer are: 1) If the multimodal treatment which includes anti-PD-1 immunotherapy and local therapies will improve the survival of this group of patients. 2) If the multimodal treatment which includes anti-PD-1 immunotherapy and local therapies can be performed safely in this group of patients. Participants will receive short course hypofractionated radiotherapy (HFRT) for the primary lesion, HFRT or stereotactic body radiotherapy (SBRT) for metastatic lesions, combined with systemic chemotherapy and anti-PD-1 immunotherapy. For patients with HER2-positive cancer (defined as IHC 3+ or 2+/ISH+), trastuzumab is used along with chemotherapy and anti-PD-1 antibody. Then, surgical resections of primary and metastatic lesions are performed as much as possible. For patients who need a widely invasive surgical approach or are inoperable, local ablative therapies such as radiofrequency ablation (RFA) and microwave ablation (MVA) can be alternatives. For patients undergoing surgical resections, postoperative treatment includes chemotherapy, which is determined by the researcher, and PD-1 antibody, which will be maintained until one year after surgery.

Conditions

Adenocarcinoma; Stomach Neoplasm; Gastroesophageal-junction Cancer; Oligometastatic Disease; Metastatic Cancer; Metastatic Gastric Cancer; Adenocarcinoma of the Stomach; Gastroesophageal Junction Adenocarcinoma; Metastatic Adenocarcinoma

Keywords

gastric cancer; GEJ Cancer; oligometastasis; limited metastatic; hypofractionated radiotherapy; immunotherapy; gastrectomy; metastasectomy

Outcome Measures

Primary Outcomes (1)

• Overall survival (OS)

  The time from enrollment to death due to any reason.

  From the time of enrollment, assessed up to 5 years follow-up.

Secondary Outcomes (6)

• No evidence of disease (NED) rate

  Assessed 1 year after treatment

• Objective response rate (ORR)

  From the time of enrollment, assessed up to 5 years follow-up.

• Progression-free survival (PFS)

  From the time of enrollment, assessed up to 5 years follow-up.

• Toxicities

  From the time of enrollment, assessed up to 28 days after the last dose of study therapy

• Surgical morbidity

  During or one month after surgery

Study Arms (1)

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

EXPERIMENTAL

Participants will receive short course hypofractionated radiotherapy (HFRT) for the primary lesion, HFRT or stereotactic body radiotherapy (SBRT) for metastatic lesions, combined with systemic chemotherapy and anti-PD-1 immunotherapy. For patients with HER2-positive cancer (defined as IHC 3+ or 2+/ISH+), trastuzumab is used along with chemotherapy and anti-PD-1 antibody. Then, surgical resections of primary and metastatic lesions are performed as much as possible. For patients who need a widely invasive surgical approach or are inoperable, local ablative therapies such as radiofrequency ablation (RFA) and microwave ablation (MVA) can be alternatives. For patients undergoing surgical resections, postoperative treatment includes chemotherapy, which is determined by the researcher, and PD-1 antibody, which will be maintained until one year after surgery.

Radiation: Radiotherapy targeted to the primary lesion; Radiation: Radiotherapy targeted to the metastatic lesions; Biological: Anti-PD-1 monoclonal antibody; Biological: Trastuzumab; Drug: Chemotherapy; Procedure: R0 total/subtotal gastrectomy with D2 lymphadenectomy; Procedure: Metastasectomy; Procedure: Local ablative therapies

Interventions

Radiotherapy targeted to the primary lesion RADIATION

5 to 7 fractions of short course hypofractionated radiotherapy (HFRT) targeted to the primary lesion.

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

Radiotherapy targeted to the metastatic lesions RADIATION

Hypofractionated radiotherapy (HFRT) or stereotactic body radiotherapy (SBRT) targeted to metastatic lesions. The target dose will be adjusted based on the lesion's site and diameter and organs at risk, with high-dose irradiation of 4-8 fractions. All metastatic lesions should be irradiated as much as possible, and partial lesion irradiation should be allowed when technically impractical.

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

Anti-PD-1 monoclonal antibody BIOLOGICAL

The anti-PD-1 mAb is used on day 1 along with each cycle of chemotherapy. There are no restrictions on the choice of anti-PD-1 mAb. Patients can choose commonly used accessible monoclonal antibodies based on their personal preferences and financial status. The commonly used anti-PD-1 mAb usages are as follows: Nivolumab/Toripalimab 240mg solution intravenously once daily, Q2W. OR Nivolumab/Toripalimab 360mg solution intravenously once daily, Q3W; OR Pembrolizumab/Tislelizumab/Sintilimab/Camrelizumab, 200mg solution intravenously once daily, Q3W.

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

Trastuzumab BIOLOGICAL

For patients with HER2-positive cancer (defined as IHC 3+ or 2+/ISH+), trastuzumab is used along with chemotherapy and anti-PD-1 antibody. The 3-weekly schedule of trastuzumab starts with a loading dose of trastuzumab of 8 mg/kg, followed by 6 mg/kg trastuzumab every 21 days.

Also known as: Herceptin®

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

Chemotherapy DRUG

The investigator's choice of chemotherapy regimens included SOX, XELOX or FOLFOX. Their usages are as follows: SOX: S-1 twice a day, days 1-14, the dose of S-1 is accorded to body-surface area (BSA): patients with a BSA of less than 1.25 m2 receive 80 mg daily; those with a BSA of 1.25 m2 or more but less than 1.5 m2 receive 100 mg daily; and those with a BSA of 1.5 m2 or more receive 120 mg daily; and oxaliplatin 130 mg/m2, day 1, every 3 weeks; XELOX: Capecitabine 1000 mg/m2 twice a day, days 1-14 and oxaliplatin 130 mg/m2, day 1, every 3 weeks; FOLFOX: Leucovorin 400 mg/m2, day 1, fluorouracil 400 mg/m2, day 1 and 1200 mg/m2, days 1-2, and oxaliplatin 85 mg/m2, day 1, every 2 weeks.

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

R0 total/subtotal gastrectomy with D2 lymphadenectomy PROCEDURE

For patients with a good response to preoperative treatment, surgical resection of primary and metastatic lesions is recommended. For primary lesions, gastrectomy with standard D2 lymphadenectomy is commonly used. The type of gastrectomy performed depends on the location and extent of the primary lesion. For GEJ or upper-third tumors, a 3 cm esophageal margin is recommended, and a total gastrectomy or esophagogastrectomy is performed. For middle-third tumors, the gastric margin is recommended to be more than 5 cm, and total gastrectomy is performed. For lower-third tumors, a 2 cm duodenal margin is recommended, and subtotal or total gastrectomy is performed. Billroth I or Roux-en-Y gastrojejunostomy is performed for distal gastrectomy patients. Roux-en-Y esophagojejunostomy is performed for patients receiving total gastrectomy.

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

Metastasectomy PROCEDURE

For patients with a good response to preoperative treatment, surgical resection of primary and metastatic lesions is recommended. For metastatic lesions, the surgical procedure and resection range are determined by the surgeon.

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

Local ablative therapies PROCEDURE

Local ablative therapies such as radiofrequency ablation (RFA) and microwave ablation (MVA) achieve high rates of complete tumor eradication of small metastases, and can be seen as alternatives if a widely invasive surgical approach is required or patient is inoperable.

Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histopathologically confirmed adenocarcinoma of stomach (G) or gastroesophageal junction (GEJ) (excluding Siewert type I).
• Limited metastatic status of disease.
• At least one evaluable lesion in CT/MRI according to RESIST 1.1 is required.
• The status of HER2 is clear.
• pMMR/MSS confirmed by immunohistochemistry or gene test.
• Male or female. Patient age ≥ 18 years and ≤ 75 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
• Physical state or organ function can tolerate the planned treatment of the study protocol, including systematic chemotherapy, immunotherapy with anti-PD-1 monoclonal antibody (mAb), primary lesion radiotherapy, metastatic lesion radiotherapy, and surgical resection of primary and/or metastatic lesions.
• No previous surgery or antitumor therapies, including chemotherapy, radiotherapy, or immunotherapy, were administered.
• Adequate hematological function: absolute neutrophil count (ANC) ≥ 1.5×109/L; platelet count ≥ 100×109/L; hemoglobin level ≥ 90 g/L.
• Adequate hepatic function: total bilirubin ≤ 1.5×upper limit of normal (ULN); AST (SGOT) and ALT (SGPT) \< 2.5 × ULN in the absence of liver metastases, or \< 5 × ULN in case of liver metastases; ALP ≤ 2.5×ULN; ALB ≥ 30 g/L.
• Adequate renal function: serum creatinine ≤ 1.5×ULN; creatinine clearance rate ≥ 60 ml/min.
• Adequate coagulation function: INR/PT ≤ 1.5×ULN; APTT ≤ 1.5×ULN.
• TSH is within the normal range; if TSH is out of the normal range, FT3 and FT4 should be investigated. If the test results of FT3/FT4 cannot be obtained, T3 and T4 can be accepted. 13. If the level of T3/T4 is normal, the patients can be selected.
• Urine test: urine protein\<2+; if the urine protein≥2+, the 24-hour urine protein quantification must be≤1g.

You may not qualify if:

• Patients who have previously received surgery, chemotherapy, radiotherapy or immunotherapy for gastric cancer.
• Patients have a history of cancer in the five years before enrollment except for squamous or basal cell carcinoma of the skin that was effectively treated and superficial bladder cancer, cervical carcinoma in situ and breast cancer in situ that was treated by operation.
• Pregnant or lactating females or females planning to become pregnant or lactating. Women of childbearing age with a positive pregnancy test or without a pregnancy test in the baseline period. Menopausal women must have stopped menstruating for at least 12 months before being considered to have no chance of pregnancy.
• Patients who had sexual activity (with the possibility of childbirth) and were unwilling to use contraception during the study period.
• Patients with a history of allergies to any drugs that may be used in this study, including chemotherapy drugs.
• History of allogeneic stem cell transplantation or organ transplantation.
• Vaccinated with live vaccine within 28 days before recruitment.
• Immunotherapy (interleukin, interferon, thymine) or other experimental treatment was given 28 days before enrollment.
• History of anti-PD-1, PD-L1, PD-L2 or any other specific T-cell costimulation or checkpoint pathway targeted therapy.
• History of using steroids (dose \> 10 mg/d prednisone) or other systemic immunosuppressive therapy within 14 days before recruitment, except for patients treated with the following regimen: steroids used for hormone replacement (dose \> 10 mg/d prednisone); local application of steroids with little systemic absorption; short-term (≤ 7 days) use of steroids to prevent allergy or vomiting.
• Patients with weight loss of more than 20% within 2 months before recruitment.
• Uncontrolled systemic diseases, including diabetes, hypertension, etc.
• Uncontrollable pleural effusion, pericardial effusion, or ascites occurred within two weeks before recruitment.
• Failure of important organs (heart, lung, liver, kidney, etc.).
• Moderate or severe renal injury \[creatinine clearance ≤ 50 ml/min (according to Cockcroft \& Gault equation)\], or SCR \> ULN.

Sponsors & Collaborators

• Fudan University: lead

Study Sites (1)

Fudan University Shanghai Cancer Center

Shanghai, China

RECRUITING

Related Publications (3)

• Al-Batran SE, Homann N, Pauligk C, Illerhaus G, Martens UM, Stoehlmacher J, Schmalenberg H, Luley KB, Prasnikar N, Egger M, Probst S, Messmann H, Moehler M, Fischbach W, Hartmann JT, Mayer F, Hoffkes HG, Koenigsmann M, Arnold D, Kraus TW, Grimm K, Berkhoff S, Post S, Jager E, Bechstein W, Ronellenfitsch U, Monig S, Hofheinz RD. Effect of Neoadjuvant Chemotherapy Followed by Surgical Resection on Survival in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Cancer: The AIO-FLOT3 Trial. JAMA Oncol. 2017 Sep 1;3(9):1237-1244. doi: 10.1001/jamaoncol.2017.0515.

  PMID: 28448662 BACKGROUND

• Al-Batran SE, Goetze TO, Mueller DW, Vogel A, Winkler M, Lorenzen S, Novotny A, Pauligk C, Homann N, Jungbluth T, Reissfelder C, Caca K, Retter S, Horndasch E, Gumpp J, Bolling C, Fuchs KH, Blau W, Padberg W, Pohl M, Wunsch A, Michl P, Mannes F, Schwarzbach M, Schmalenberg H, Hohaus M, Scholz C, Benckert C, Knorrenschild JR, Kanngiesser V, Zander T, Alakus H, Hofheinz RD, Roedel C, Shah MA, Sasako M, Lorenz D, Izbicki J, Bechstein WO, Lang H, Moenig SP. The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI. BMC Cancer. 2017 Dec 28;17(1):893. doi: 10.1186/s12885-017-3918-9.

  PMID: 29282088 BACKGROUND

• Zhou ML, Xu RN, Tan C, Zhang Z, Wan JF. Advanced gastric cancer achieving major pathologic regression after chemoimmunotherapy combined with hypofractionated radiotherapy: A case report. World J Gastrointest Oncol. 2023 Jun 15;15(6):1096-1104. doi: 10.4251/wjgo.v15.i6.1096.

  PMID: 37389115 BACKGROUND

MeSH Terms

Conditions

Adenocarcinoma; Stomach Neoplasms; Neoplasm Metastasis

Interventions

spartalizumab; Trastuzumab; Drug Therapy; Metastasectomy

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Therapeutics; Surgical Procedures, Operative

Central Study Contacts

Menglong Zhou, MD

CONTACT

86-18121299608; mrzhouml@163.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Chief Physician, Head of the First Department of Gastric Surgery, Fudan University Shanghai Cancer Center

Study Record Dates

• First Submitted: October 19, 2023
• First Posted: November 8, 2023
• Study Start: January 1, 2023
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2027
• Last Updated: November 8, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)