Safety and Efficacy of Leucine-Restricted Diet Combined With Neoadjuvant Chemotherapy and Immunotherapy in Gastric Cancer

Official title

A Study on the Safety and Efficacy of Leucine-Restricted Diet in Gastric Cancer Patients Treated With Neoadjuvant Chemotherapy and Immunotherapy

Overview

Consistent with previous literature, the investigators postulate that a leucine-restricted diet is safe and well-tolerated in gastric cancer patients receiving neoadjuvant chemo-immunotherapy. Furthermore, the investigators propose that this dietary regimen promotes the activation of immune cells within the tumor microenvironment (TME). When combined with neoadjuvant chemo-immunotherapy, it demonstrates synergistic anti-tumor efficacy, thereby improving patient prognosis.

Detailed description

In this study, participants were divided into an intervention group and a control group. Both groups received four cycles of neoadjuvant therapy comprising Oxaliplatin, S-1, and the PD-1 inhibitor Sintilimab. The intervention group implemented a 3-day leucine-restricted diet during each cycle, gradually resuming a normal diet thereafter, whereas the control group maintained a standard normal diet throughout the treatment period. This design was established to evaluate the safety and efficacy of the leucine-restricted diet in the context of neoadjuvant chemo-immunotherapy for gastric cancer.

Interventions

• Dietary supplement Leucine-restricted diet
  Patients received a total of four cycles of neoadjuvant therapy.During each treatment cycle, patients adhered to a leucine-restricted diet for 3 days. After this 3-day period, the dietary intervention was stopped, and patients gradually resumed a normal diet for the remainder of the cycle.

Primary outcome measures

• Response Evaluation Criteria in Solid Tumors (RECIST) Grade [Time frame: 1 year after surgery]
• 1-year survival rate and overall survival (OS) [Time frame: 1 year after surgery]
• The tumor regression grade (TRG) system [Time frame: 1 month after surgery]
• Grade of CTCAE grading system [Time frame: 6 months after surgery]

Secondary outcome measures (2)

• Serum amino acid concentrations in patients [Time frame: Measurements were performed prior to the initiation of the amino acid-restricted diet and on the day of surgery before the operation.]
• Changes in the Immune Microenvironment [Time frame: Measurements were performed prior to the initiation of the amino acid-restricted diet and on the day of surgery before the operation]

Eligibility criteria

Inclusion criteria

• Pathological Confirmation: Histologically confirmed locally advanced gastric cancer.
• Demographics: Aged 18 to 70 years, inclusive, regardless of gender.
• Dietary Capability: Capable of oral intake or receiving a liquid diet via nasogastric tube.
• Consent: Willing to participate in the study and have signed the Written Informed Consent Form (ICF).
• Staging and Treatment Indication: No evidence of distant metastasis on imaging examinations (such as CT or PET-CT), with a clinical stage of locally advanced gastric cancer, indicating the need for neoadjuvant chemo-immunotherapy prior to surgery.
• Exclusion of Other Malignancies: No concurrent primary malignant tumors other than gastric cancer.

Exclusion criteria

• Cognitive or Psychiatric Impairment: Cognitive dysfunction or psychiatric disorders severe enough to prevent the patient from understanding the study content or providing informed consent.
• Diabetes Mellitus: Diagnosis of Type 1 or Type 2 diabetes mellitus.
• Gastrointestinal Conditions: Presence of severe diarrhea, intractable vomiting, severe malabsorption syndrome, paralytic or mechanical intestinal obstruction, or active gastrointestinal bleeding.
• Allergy/Hypersensitivity: Known hypersensitivity or allergy to any of the main components of the leucine-deficient nutritional powder.
• Concomitant Supplements: Current use of other nutritional supplements that may potentially confound the study results or affect the evaluation of efficacy.
• Treatment Tolerance: Inability to tolerate neoadjuvant chemo-immunotherapy, or occurrence of severe gastrointestinal adverse events following such treatment.
• Pathological Diagnosis: Postoperative pathological diagnosis confirming non-primary gastric cancer (e.g., metastatic tumors from other origins).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 1 center

• Qilu Hospital of Shandong University — Jinan

Publications

• Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39-68. doi: 10.1146/annurev-immunol-020711-075024. Epub 2011 Nov 29. PMID 22136167
• Delgoffe GM, Powell JD. mTOR: taking cues from the immune microenvironment. Immunology. 2009 Aug;127(4):459-65. doi: 10.1111/j.1365-2567.2009.03125.x. PMID 19604300
• Passarelli MC, Pinzaru AM, Asgharian H, Liberti MV, Heissel S, Molina H, Goodarzi H, Tavazoie SF. Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics. Nat Cell Biol. 2022 Mar;24(3):307-315. doi: 10.1038/s41556-022-00856-5. Epub 2022 Mar 14. PMID 35288656
• Saito Y, Li L, Coyaud E, Luna A, Sander C, Raught B, Asara JM, Brown M, Muthuswamy SK. LLGL2 rescues nutrient stress by promoting leucine uptake in ER+ breast cancer. Nature. 2019 May;569(7755):275-279. doi: 10.1038/s41586-019-1126-2. Epub 2019 Apr 17. PMID 30996345
• Wang N, Lu S, Cao Z, Li H, Xu J, Zhou Q, Yin H, Qian Q, Zhang X, Tao M, Jiang Q, Zhou P, Zheng L, Han L, Li H, Yin L, Gu Y, Dou X, Sun H, Wang W, Piao HL, Li F, Xu Y, Yang W, Chen S, Liu J. Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism. Cell Metab. 2025 Jun 3;37(6):1381-1399.e9. doi: 10.1016/j.cmet.2025.02.008. Epub 2025 Mar 19. PMID 40112809
• Wang Z, Lu Z, Lin S, Xia J, Zhong Z, Xie Z, Xing Y, Qie J, Jiao M, Li Y, Wen H, Zhao P, Zhang D, Zhou P, Qian J, Luo F, Wang L, Yu H, Liu J, Gu J, Liu R, Chu Y. Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion. Immunity. 2022 Jun 14;55(6):1067-1081.e8. doi: 10.1016/j.immuni.2022.04.017. Epub 2022 Jun 3. PMID 35659337
• Tong H, Jiang Z, Song L, Tan K, Yin X, He C, Huang J, Li X, Jing X, Yun H, Li G, Zhao Y, Kang Q, Wei Y, Li R, Long Z, Yin J, Luo Q, Liang X, Wan Y, Zheng A, Lin N, Zhang T, Xu J, Yang X, Jiang Y, Li Y, Xiang Y, Zhang Y, Feng L, Lei Z, Shi H, Ma X. Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation. Cell Metab. 2024 Dec 3;36(12):2493 PMID 39577415
• Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, Richie JP Jr, Ciccarella A, Calcagnotto A, Mikhael PG, Mentch SJ, Liu J, Ables G, Kirsch DG, Hsu DS, Nichenametla SN, Locasale JW. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature. 2019 Aug;572(7769):397-401. doi: 10.1038/s41586-019-1437-3. Epub 2019 Jul 31. PMID 31367041

Identifiers

NCT: NCT07537361 · KYLL-202509-010-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗