Synergistic Effects of PD-1 Antibody and Chemotherapy Followed by Surgery in Limited-metastatic G/GEJ Adenocarcinoma

Gastric Cancer Clinical Trial

— ROSETTE  

Official title:

Synergistic Effects of PD-1 Antibody and Chemotherapy Followed by Surgery in Patients With Limited-metastatic Gastric or Gastroesophageal Adenocarcinoma: an Open-label, Single-center, Phase 2 Trial (ROSETTE Trial)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06468280
• Other study ID #: KY2024164
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: July 2024
• Est. completion date: July 2028

Study information

• Verified date: June 2024
• Source: Shanghai Zhongshan Hospital
• Contact: Xuefei Wang, MD, PhD
• Phone: 0
• Email: wang.xuefei[@]zs-hospital.sh.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective of this trial is to compare the efficacy of a comprehensive treatment strategy involving PD-1 monoclonal antibody combined with XELOX chemotherapy followed by radical resection surgery, versus simple systemic treatment in patients with limited distant metastasis of gastric adenocarcinoma/gastroesophageal junction adenocarcinoma.

After enrollment and successful screening, eligible participants will be randomized in a 1:1 ratio into a surgical arm and a non-surgical arm, and will undergo the following treatment:

Surgical Arm:

1. Phase 1 Systemic Therapy: Administration of PD-1 monoclonal antibody in combination with XELOX chemotherapy for cycles 1-4.

2. Surgery: Performing a D2 standard gastrectomy for gastric cancer and radical resection of resectable metastatic lesions.

3. Phase 2 Systemic Therapy: Continuation of PD-1 monoclonal antibody combined with XELOX chemotherapy for cycles 5-8, followed by maintenance therapy with PD-1 monoclonal antibody and capecitabine monotherapy from the 9th cycle until two years post-enrollment.

4. During phase 2 systemic therapy, concurrent local treatments for unresected metastatic lesions are permitted, including radiotherapy, interventional embolization, radiofrequency ablation, and hyperthermic intraperitoneal chemotherapy (HIPEC).

Non-Surgical Arm:

1. Phase 1 Systemic Therapy: Administration of PD-1 monoclonal antibody in combination with XELOX chemotherapy for cycles 1-4.

2. Phase 2 Systemic Therapy: Continuation of PD-1 monoclonal antibody combined with XELOX chemotherapy for cycles 5-8, followed by maintenance therapy with PD-1 monoclonal antibody and capecitabine monotherapy from the 9th cycle until two years post-enrollment.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 82
• Est. completion date: July 2028
• Est. primary completion date: July 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Male or female, aged =18 and =75 years.

2. Pathologically confirmed gastric adenocarcinoma or esophagogastric junction adenocarcinoma (limited to Siewert II and III types), with known PD-L1 expression status.

3. HER2-negative gastric cancer.

4. Mismatch repair function intact (pMMR) or microsatellite stable (MSS) gastric cancer.

5. Investigator-assessed resectability of the primary gastric cancer with limited distant metastasis, fulfilling the following criteria with either (A) or a single (B)±(A):

(A). Non-regional intra-abdominal lymph node metastasis: Includes metastasis to the superior mesenteric artery, middle colic artery, and para-aortic/retroperitoneal nodes (according to AJCC 8th edition standards). However, metastasis limited to the 16a2 and/or 16b1 groups does not qualify as distant nodal group metastasis for this study.

(B1).Localized peritoneal metastasis (P0CY1, P1a, or P1b, according to the Japanese Gastric Cancer Treatment Guidelines, 15th edition)

• P0CY1: Malignant cells detected in ascites or peritoneal lavage during laparoscopy, without visible peritoneal metastases.

• P1a: Metastasis confined to the peritoneum adjacent to structures such as the stomach, greater and lesser omentum, anterior leaf of the transverse mesocolon, pancreatic capsule, and spleen.

• P1b: Metastasis confined to the peritoneum in the upper abdomen, involving the parietal peritoneum above the umbilicus and the visceral peritoneum region above the transverse colon.

(B2).Liver metastasis: Up to 5 metastatic lesions. (B3).Lung metastasis: Up to 5 unilateral metastatic lesions. (B4).Ovarian metastasis: Unilateral or bilateral. (B5).Adrenal metastasis: Unilateral or bilateral. (B6).Single-region extra-abdominal lymph node metastasis: Such as cervical, supraclavicular, or mediastinal lymph nodes.

(B7).Bone metastasis limited to a single radiation field. (B8).Other limited metastases as determined by the research team.

6. No prior anti-tumor treatment before enrollment.

7. Eastern Cooperative Oncology Group (ECOG) performance status =2, and no contraindications to surgery.

8. Life expectancy of at least 3 months.

9. Feasibility of physical condition and organ function for major abdominal surgery.

10. Blood routine and biochemical indicators within the following standards within 7 days prior to enrollment:

• White blood cell count (WBC) >4.0×109/L, absolute neutrophil count (ANC) >1.5×109/L, hemoglobin (Hb) =90 g/L, platelets (PLT) =100×109/L;

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =2.5× upper limit of normal (ULN); total bilirubin (TBIL) =1.5×ULN;

• Serum creatinine (Cr) =1.5×ULN or estimated glomerular filtration rate (eGFR) =60 ml/min/1.73m2; serum albumin (ALB) =30 g/L;

• International normalized ratio (INR) or prothrombin time (PT) =1.5×ULN, activated partial thromboplastin time (aPTT) =1.5×ULN for subjects not receiving anticoagulant therapy; PT values within the expected therapeutic range for subjects receiving anticoagulant therapy;

11. Willingness and ability to comply with the study protocol during the study period.

12. Females of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to enrollment, and must agree to use highly effective contraception during the study period and for at least 180 days after receiving the last dose of study medication; unsterilized males must agree to use highly effective contraception during the study period and for at least 180 days after receiving the last dose of study medication.

13. Written informed consent will be provided before entering the study, and patients must understand they can withdraw from the study anytime without consequences.

Exclusion Criteria:

1. Borrmann type III, defined as ulcerative infiltrative gastric cancer with a diameter exceeding 8 cm, or type IV, defined as diffuse infiltrative gastric cancer.

2. Inability to tolerate oral chemotherapy.

3. Gastric cancer limited to the mucosal or submucosal layer, solely combined with ovarian metastatic tumors.

4. Presence of central nervous system metastasis and/or carcinomatous meningitis.

5. Allergy to any component of the drugs involved in this study.

6. History of or current concurrent malignancy, except for completely excised basal cell or squamous cell skin cancer, superficial bladder cancer, cervical or breast carcinoma in situ, with at least 5 years without recurrence.

7. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage within 14 days prior to enrollment.

8. Weight loss =20% within 2 months prior to enrollment.

9. Upper gastrointestinal obstruction or physiological dysfunction.

10. Prior cytotoxic chemotherapy, radiotherapy, immunotherapy, or radical surgery for the current gastric cancer, except corticosteroids.

11. Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, or any other specific antibodies or drugs targeting T cell co-stimulation or checkpoint pathways.

12. Requirement of systemic corticosteroids (at a dose higher than 10 mg/d of prednisone or equivalent) or other immunosuppressive agents for systemic therapy within 14 days prior to enrollment.

13. Administration of live vaccines within 4 weeks prior to enrollment (Note: Seasonal influenza vaccines are typically inactivated vaccines and are allowed for use; intranasal vaccines are live vaccines and are not allowed for use).

14. Uncontrolled systemic diseases, including diabetes and hypertension.

15. Active autoimmune diseases or history of autoimmune diseases with potential for recurrence.

16. Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis and human immunodeficiency virus (HIV) infection.

17. History of lung diseases, including interstitial lung disease, non-infectious pneumonia, pulmonary fibrosis, and acute lung disease.

18. Currently planning to conceive, pregnant, or in the lactation period.

19. Hepatitis B surface antigen (HBsAg) carrier with hepatitis B virus (HBV) DNA =500 IU/mL.

20. Positive tests for HIV-1 antibody, HIV-2 antibody, human T-lymphotropic virus-1 (HTLV-1) antibody, or positive RNA test for hepatitis C virus (HCV).

21. Any disease or condition deemed by the investigator to potentially affect study compliance, informed consent signing, or suitability for participation in this clinical study.

Related Conditions & MeSH terms

• Adenocarcinoma
• Gastric Cancer
• GastroEsophageal Cancer

Intervention

Procedure:
• Radical surgery
Radical gastrectomy with standard D2 lymphadenectomy will be performed, along with radical surgery for resectable metastatic lesions.

Drug:
• PD-1 Monoclonal Antibody
PD-1 monoclonal antibody will be administered at a dosage of 20 mg/kg via intravenous infusion, once every cycle, each cycle spanning three weeks. The investigators will select the specific PD-1 antibody utilized based on clinical considerations, which may include sintilimab, toripalimab, or nivolumab.
• XELOX Chemotherapy Regimen
Oxaliplatin: 130 mg/m² administered via a 3-hour intravenous infusion on D1 of each 3-week cycle. Capecitabine: 1000 mg/m² taken orally twice daily. The first dose is administered on the evening of D1, and the last dose on the morning of D15, consisting of 2 weeks of treatment and a 1-week break in each 3-week cycle.

Procedure:
• Local Treatment
Additional local treatment for unresected metastatic lesions during phase 2 systemic therapy is permitted, including: Bone metastasis, distant lymph nodes, adrenal metastasis: Radiation therapy. Lung and liver metastasis: Radiofrequency ablation, interventional embolization, or radiation therapy. Peritoneal metastasis: Hyperthermic intraperitoneal chemotherapy (HIPEC). Other metastatic lesions: Non-surgical treatment options discussed by the multidisciplinary team.

Locations

Country	Name	City	State
China	Zhongshan Hospital Fudan University	Shanghai	Shanghai City

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Zhongshan Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-Free Survival (EFS) Rate	Defined as the time from randomization to the first occurrence of any event, including disease progression (local progression, local recurrence, progression of existing distant metastatic lesions, or the emergence of new distant metastases) or death from any cause.	1 year from the time of randomization
Secondary	Objective Response Rate (ORR)	The proportion of subjects achieving complete response (CR) or partial response (PR) after completing phase I systemic treatment.	From randomization to the date of completing phase 1 systemic treatment, an average of 12 weeks.
Secondary	Disease Control Rate (DCR)	The proportion of subjects achieving CR, PR, or stable disease (SD) after completing phase I systemic treatment.	From randomization to the date of completing phase 1 systemic treatment, an average of 12 weeks.
Secondary	Pathological Complete Response (pCR) Rate	The proportion of surgical cohort subjects with no residual tumor cells and no positive lymph nodes (ypT0N0) in the primary tumor specimen. Non-surgical subjects in the surgical cohort are considered non-pCR.	From randomization to the date of surgery, an average of 14 weeks.
Secondary	Major Pathologic Response Rate (MPR)	The proportion of surgical cohort subjects with residual tumor cells <10% in the primary tumor specimen based on the Becker tumor regression grading (TRG) standard (1a-1b). Non-surgical subjects in the surgical cohort are considered non-MPR.	From randomization to the date of surgery, an average of 14 weeks.
Secondary	R0 Resection Rate	R0 resection is defined as no tumor at the gross or microscopic resection margins following standard D2 lymphadenectomy gastrectomy.	From randomization to the date of surgery, an average of 14 weeks.
Secondary	Overall Survival (OS)	Time from randomization to death from any cause. Survivors are censored at the last known survival date.	Up to 4 years follow-up