Trial Title:
Radiotherapy + Chemoimmunotherapy Followed by Surgery in Patients With Limited Metastatic Gastric or GEJ Cancer
NCT ID:
NCT06121700
Condition:
Adenocarcinoma
Stomach Neoplasm
Gastroesophageal-junction Cancer
Oligometastatic Disease
Metastatic Cancer
Metastatic Gastric Cancer
Adenocarcinoma of the Stomach
Gastroesophageal Junction Adenocarcinoma
Metastatic Adenocarcinoma
Conditions: Official terms:
Adenocarcinoma
Stomach Neoplasms
Esophageal Neoplasms
Trastuzumab
Antibodies
Antibodies, Monoclonal
Conditions: Keywords:
gastric cancer
GEJ Cancer
oligometastasis
limited metastatic
hypofractionated radiotherapy
immunotherapy
gastrectomy
metastasectomy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
Radiotherapy targeted to the primary lesion
Description:
5 to 7 fractions of short course hypofractionated radiotherapy (HFRT) targeted to the
primary lesion.
Arm group label:
Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection
Intervention type:
Radiation
Intervention name:
Radiotherapy targeted to the metastatic lesions
Description:
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.
Arm group label:
Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection
Intervention type:
Biological
Intervention name:
Anti-PD-1 monoclonal antibody
Description:
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.
Arm group label:
Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection
Intervention type:
Biological
Intervention name:
Trastuzumab
Description:
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.
Arm group label:
Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection
Other name:
Herceptin®
Intervention type:
Drug
Intervention name:
Chemotherapy
Description:
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.
Arm group label:
Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection
Intervention type:
Procedure
Intervention name:
R0 total/subtotal gastrectomy with D2 lymphadenectomy
Description:
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.
Arm group label:
Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection
Intervention type:
Procedure
Intervention name:
Metastasectomy
Description:
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.
Arm group label:
Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection
Intervention type:
Procedure
Intervention name:
Local ablative therapies
Description:
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.
Arm group label:
Radiotherapy, Chemotherapy and anti-PD-1 Immunotherapy followed by Surgical Resection
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Histopathologically confirmed adenocarcinoma of stomach (G) or gastroesophageal
junction (GEJ) (excluding Siewert type I).
2. Limited metastatic status of disease.
3. At least one evaluable lesion in CT/MRI according to RESIST 1.1 is required.
4. The status of HER2 is clear.
5. pMMR/MSS confirmed by immunohistochemistry or gene test.
6. Male or female. Patient age ≥ 18 years and ≤ 75 years.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
8. 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.
9. No previous surgery or antitumor therapies, including chemotherapy, radiotherapy, or
immunotherapy, were administered.
10. Adequate hematological function: absolute neutrophil count (ANC) ≥ 1.5×109/L;
platelet count ≥ 100×109/L; hemoglobin level ≥ 90 g/L.
11. 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.
12. Adequate renal function: serum creatinine ≤ 1.5×ULN; creatinine clearance rate ≥ 60
ml/min.
13. Adequate coagulation function: INR/PT ≤ 1.5×ULN; APTT ≤ 1.5×ULN.
14. 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.
15. Urine test: urine protein<2+; if the urine protein≥2+, the 24-hour urine protein
quantification must be≤1g.
16. There is no serious concomitant disease, and the patient's life expectancy is more
than 6 months.
17. Patients agree to sign written informed consent before recruitment.
18. Patients are willing and able to follow the protocol during the study, including
receiving treatment and scheduled follow-up and examination.
19. Patients are willing to provide samples of blood and tissue.
20. Female patients should not be pregnant or breast feeding.
21. Female patients agree to take contraceptive measures during treatment and within 120
days after the last dose of anti-PD-1 mAb or 180 days after the last use of
chemotherapy or radiotherapy.
Definition of the limited metastatic disease:
1. Retroperitoneal lymph node metastases (RPLM) only or at maximum one organ involved
with or without RPLM.
2. There is no peritoneal seeding on diagnostic laparoscopy (P0).
3. The definition of RPLM includes but is not limited to para-aortal,
intra-aorto-caval, parapancreatic or mesenteric lymph nodes. If the duodenum is
invaded, retropancreatic nodes are not regarded as M1.
4. The definition of single organ metastasis in the study is as follows: a) Liver:
maximum of 5 metastatic lesions that are potentially resectable and the metastases
should be limited to one lobe and not involve important blood vessels or bile ducts.
b) Lung: unilateral involvement, potentially resectable. c) Ovary: uni- or bilateral
Krukenberg tumors in the absence of macroscopic peritoneal carcinomatosis. d)
Adrenal gland: uni- or bilateral metastases. e) Extra-abdominal lymph node
metastases, such as supraclavicular or cervical lymph node involvement. f) Bone:
localized bone involvement (defined as being within one radiation field).
5. Other metastatic disease locations are considered, limited by the investigator and
confirmed by the multidisciplinary team (MDT).
Exclusion Criteria:
1. Patients who have previously received surgery, chemotherapy, radiotherapy or
immunotherapy for gastric cancer.
2. 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.
3. 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.
4. Patients who had sexual activity (with the possibility of childbirth) and were
unwilling to use contraception during the study period.
5. Patients with a history of allergies to any drugs that may be used in this study,
including chemotherapy drugs.
6. History of allogeneic stem cell transplantation or organ transplantation.
7. Vaccinated with live vaccine within 28 days before recruitment.
8. Immunotherapy (interleukin, interferon, thymine) or other experimental treatment was
given 28 days before enrollment.
9. History of anti-PD-1, PD-L1, PD-L2 or any other specific T-cell costimulation or
checkpoint pathway targeted therapy.
10. 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.
11. Patients with weight loss of more than 20% within 2 months before recruitment.
12. Uncontrolled systemic diseases, including diabetes, hypertension, etc.
13. Uncontrollable pleural effusion, pericardial effusion, or ascites occurred within
two weeks before recruitment.
14. Failure of important organs (heart, lung, liver, kidney, etc.).
15. Moderate or severe renal injury [creatinine clearance ≤ 50 ml/min (according to
Cockcroft & Gault equation)], or SCR > ULN.
16. Dipyrimidine dehydrogenase (DPD) deficiency.
17. Patients with central nervous system (CNS) disorders or tumors, including brain
metastases, peripheral nervous system disorders or psychiatric diseases.
18. Cerebrovascular accidents occurred within 6 months before recruitment.
19. Patients with peripheral neuropathy of NCI-CTCAE grade 1, except for those with
disappearance of the deep tendon reflex.
20. Patients with a known history of uncontrolled or symptomatic angina, uncontrolled
arrhythmias and hypertension, congestive heart failure, cardiac infarction or
cardiac insufficiency within 6 months prior to study recruitment.
21. Pulmonary embolism occurred within 28 days before enrollment.
22. Patients who had the following history of pulmonary diseases: interstitial lung
disease, noninfectious pneumonia, pulmonary fibrosis, or acute lung disease.
23. Patients with gastrointestinal bleeding or a high risk of bleeding within the first
2 weeks of enrollment.
24. Patients who experienced gastrointestinal perforation or fistula within 6 months
prior to enrollment.
25. Upper gastrointestinal obstruction, dysfunction or malabsorption syndrome may affect
the absorption of oral chemotherapy drugs.
26. Patients who cannot swallow or take medication orally.
27. Patients with a history of active autoimmune disease or refractory autoimmune
disease.
28. Severe chronic or active infections requiring systemic antibiotics, antifungal or
antiviral therapy, including tuberculosis and AIDS.
29. Known history of human immunodeficiency virus (HIV) infection.
30. Patients with untreated chronic hepatitis B or HBV-DNA exceeding 500 IU/ml or
HCV-RNA positive.
31. Alcohol/drug abuse and medical, psychological or social conditions may interfere
with patients' participation in the study or have an impact on the evaluation of the
study results.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Fudan University Shanghai Cancer Center
Address:
City:
Shanghai
Country:
China
Status:
Recruiting
Contact:
Last name:
Menglong Zhou, MD
Phone:
86-18121299608
Email:
mrzhouml@163.com
Investigator:
Last name:
Dazhi Xu, MD
Email:
Principal Investigator
Investigator:
Last name:
Zhen Zhang, MD
Email:
Sub-Investigator
Start date:
January 1, 2023
Completion date:
December 31, 2027
Lead sponsor:
Agency:
Fudan University
Agency class:
Other
Source:
Fudan University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06121700
