Additional synbiotics to combination therapy with immune checkpoint inhibitors for unresectable or recurrent gastric and esophageal cancer

JRCT ID: jRCTs051230063

Registered date:04/07/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Gastric cancer , esophageal cancer
• Date of first enrollment: 04/07/2023
• Target sample size: 244
• Study type: Interventional
• Intervention(s): Synprotec or placebo is administered orally 3 times daily after each meal, starting at least 5 days before the start of chemotherapy and continuing for 6 months after the start of chemotherapy or until the end of first-line therapy, whichever is shorter.

Outcome(s)

• Primary Outcome: Progression free survaival

Secondary Outcome

(1) Progression free survival for gastric cancer
(2) Progression free survival for esophageal cancer
(3) Objective resoponce rate of 1st line chemotherapy
(4) Adverse events during 1st line chemotherapy
(5) Duration of response
(6) Time to treatment failure
(7) Relative Dose Intensity
(8) Intestinal environmental index
(9) iPFS
(10) Overall survival
(11) Best response according to iRECIST

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: < 85age old
• Gender: Both

Include criteria

(1) Gastric cancer histologically diagnosed as adenocarcinoma (papillary adenocarcinoma, tubular adenocarcinoma, poorly differentiated adenocarcinoma), signet ring cell carcinoma, mucinous carcinoma, or hepatoid adenocarcinoma.
Esophageal cancer histologically diagnosed as squamous cell carcinoma, adenosquamous cell carcinoma, adenocarcinoma, or basaloid carcinoma.
(2) Subjects with unresectable advanced gastric cancer/esophageal cancer or recurrent gastric cancer/esophageal cancer who undergo ICI+chemotherapy or ICI combination therapy, which is the first-line treatment, as usual clinical practice.
[1] In the case of unresectable advanced gastric cancer, those who satisfy both i) and ii) below.
i) Diagnosed as cStage IVB or pStage IV based on clinical or surgical findings. However, it does not include the case of stage IV only by peritoneal washing cytology (CY1). Also, it does not include localized peritoneal dissemination or cases in which macroscopic cure was achieved by excision of para-aortic lymph node metastasis.
ii) Non-surgical cases judged not to be suitable for surgery based on clinical findings including diagnostic imaging, or surgical cases in which gastrectomy was performed but ended in R1/2 resection. For those who underwent gastrectomy but ended up with R1/2 resection, more than 2 weeks had passed since the date of surgery. However, cases with positive resection margins and positive peeled surfaces are not included.
[2] In the case of recurrent gastric cancer, the following are satisfied.
Gastric cancer with recurrence after radical resection based on clinical findings (including imaging findings) or surgical findings.
However, the following cases are excluded.
i) Recurrent cases during adjuvant therapy such as TS1 or within 6 months after adjuvant therapy
ii) recurrence within 6 months after preoperative chemotherapy
[3] In the case of unresectable esophageal cancer, either i) or ii) below is satisfied.
i) Distant metastasis other than #104 (supraclavicular lymph node).
ii) Wall invasion depth cT4b (UICC-TNM 8th edition).
[4] In case of recurrent esophageal cancer, the following are satisfied.
Esophageal cancer with recurrence after radical resection due to clinical or surgical findings.
Patients receiving nivolumab as postoperative adjuvant therapy are excluded.
Exclude recurrence cases within 6 months after preoperative chemotherapy
Exclude recurrent cases within 6 months after chemoradiotherapy
However, cases of radiotherapy alone may be eligible
(3) Aged 18 to 85 at the time of obtaining consent
(4) Subjects who can take oral intake. Dysphagia score <= 2 (semi-solid or firmer food intake possible). However, if the administration route of Synprotec is secured by bypass surgery, gastrostomy, enterostomy, etc., even those with a Dysphagia score > 2 are eligible.
(5) Performance status (ECOG) is either 0 or 1
(6) Subjects who have the latest test values within 14 days before registration (same day of the week 2 weeks before the registration date is acceptable) and satisfy all of the following.
-Neutrophil count => 1,500 /mm3
-Platelet count => 10x10000/mm3
-Total bilirubin <= 1.5 mg/dL
-AST (GOT) <= 100 IU/L (<= 200 IU/L with liver metastases)
-ALT (GPT) <= 100 IU/L (<= 200 IU/L if there is liver metastasis)
-Renal function:
Ccr => 50 mL/min
CCr should be 50 mL/min or more as calculated by the Cockcroft-Gault formula.
If the calculated value is less than 50 mL/min, it will be considered eligible if the measured value is confirmed to be 50 mL/min or more.
(7) Subjects who can obtain a written consent from him/herself for participation in this research.

Exclude criteria

(1) Subjects with active multiple cancers (simultaneous multiple cancers and metachronous multiple cancers with a disease-free period of less than 5 years. However, carcinoma in situ judged to be cured by local treatment and lesions equivalent to intramucosal carcinoma are not included in active double cancer).
(2) Subjects with an indwelling gastrointestinal stent (esophageal stent, etc.)
(3) Subjects with infectious diseases requiring systemic treatment.
(4) Pregnant women, those who may become pregnant, or women who are breastfeeding.
(5) Subjects with psychosis or psychiatric symptoms and judged to be difficult to participate in this study.
(6) Subjects with poorly controlled diabetes.
(7) Subjects with unstable angina pectoris (angina pectoris with onset or exacerbation within the last 3 weeks) or a history of myocardial infarction within 6 months.
(8) Subjects with serious complications (renal failure, liver failure, interstitial pneumonia/pulmonary fibrosis).
(9) Subjects with active bleeding.
(10) Subjects with history of treatment with anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody, or other antibody therapy or drug therapy for the purpose of controlling T cells.
(11) HER2-positive (HER2 2+ and FISH-positive or HER2 3+) gastric cancer patients
(12) Subjects with brain metastasis.
(13) Subjects with symptomatic bone metastases at enrollment.
(14) Subjects with comorbidity or history of thyroid dysfunction.
(15) Subjects with comorbidity or history of autoimmune disease.
(16) Subjects who have received administration of systemic adrenocortical hormone exceeding 10 mg/day in terms of prednisolone (excluding temporary use for the purpose of examination or preventive administration) or immunosuppressants within 14 days prior to registration .
(17) Subjects with milk allergy.
(18) Subjects who are participating in other interventional study.However, if the primary endpoint is not survival, and the principal investigator determines that duplicate enrollment is possible, it is acceptable.
(19) Subjects who are judged to be inappropriate as research subjects by the investigator for other reasons.

Related Information

• Primary Sponsor: Kurokawa Yukinori
• Secondary Sponsor: Doki Yuichiro
• Source(s) of Monetary Support: Yakult Honsha Co.,Ltd.