Fasting-Mimicking Diet Combined With IO-TKI Combination Therapy in Patients With Metastatic Renal Cell Carcinoma

FMD is a plant-based diet that is low in protein and carbohydrates but higher in healthy fats. For 3 to 7 days at a time, people eat less than 1,100 calories per day. The goal is to copy some of the helpful effects that complete fasting has on slowing cancer cell growth, while avoiding the problems of full fasting such as extreme hunger or malnutrition.

In laboratory studies with mice, FMD has been shown to work like water-only fasting to fight tumors. When combined with chemotherapy, immunotherapy, or targeted therapy, it can slow tumor growth and help the mice live longer.

For advanced kidney cancer, the usual first treatment is a combination of targeted therapy plus immunotherapy. Researchers want to find out if adding FMD to this standard treatment can help patients live longer and feel better.

Inclusion criteria

• Subjects voluntarily participate in the study and sign the informed consent form.
• Age ≥ 18 years at the time of signing the informed consent form; males or females are eligible.
• Pathologically confirmed advanced renal cell carcinoma (metastatic or unresectable) with predominant clear cell histology.
• No prior systemic anti-tumor therapy (except for cytokine therapy).
• At least one measurable target lesion according to RECIST v1.1 criteria (confirmed by CT or MRI).
• Body mass index (BMI) ≥ 20 kg/m².
• IMDC intermediate- or poor-risk group.
• Willing and able to comply with the fasting-mimicking diet (FMD)protocol,scheduled visits, treatment plan, laboratory tests, and other study procedures.
• Able to maintain daily contact with the investigator (via telephone or email) to communicate key clinical information, including daily body weight, blood pressure, health status, and adverse events during the 5-day FMD period.
• Low nutritional risk according to the Nutritional Risk Screening (NRS) tool.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adequate organ function within 7 days prior to the first dose of study drug (no blood products, hematopoietic growth factors, leukocyte- or platelet-stimulating agents allowed in the 7 days prior to laboratory testing):

Absolute neutrophil count ≥ 1.5 × 10⁹/L Platelets ≥ 100 × 10⁹/L Hemoglobin ≥ 90 g/L Serum albumin ≥ 30 g/L AST and ALT ≤ 2.5 × upper limit of normal (ULN); if liver metastases are present, AST and ALT ≤ 5 × ULN Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN allowed for subjects with Gilbert syndrome) Serum creatinine ≤ 1.5 × ULN; if > 1.5 × ULN, creatinine clearance (CLcr) calculated by Cockcroft-Gault formula must be ≥ 50 mL/min Left ventricular ejection fraction (LVEF) > 50% Proteinuria < 2+ (if ≥ 2+, 24-hour urine protein quantification must be < 1 g) International normalized ratio (INR) ≤ 1.5 × ULN or prothrombin time (PT) prolongation ≤ 1.5 × ULN; activated partial thromboplastin time (APTT) ≤ 1.5 × ULN

• No plans for pregnancy during the study period.

Exclusion criteria

• Prior receipt of any systemic anti-tumor therapy for renal cell carcinoma (RCC), including systemic chemotherapy, anti-angiogenic therapy, molecular targeted therapy, immunotherapy containing anti-CTLA-4, anti-PD-1/PD-L1 monoclonal antibodies, and immune checkpoint agonist antibodies (e.g., anti-ICOS, anti-CD40, anti-CD137, anti-GITR, or anti-OX40 antibodies).
• Unintentional weight loss ≥5% within the past 3 months, unless the patient has BMI >22 kg/m² and weight loss at study entry is <10%; or unintentional weight loss ≥10% within the past 3 months, unless the patient has BMI >25 kg/m² and weight loss at study entry is <15% (in both cases, body weight must have been stable for at least 1 month prior to study entry).
• Body mass index (BMI) <20 kg/m².
• Moderate or high nutritional risk according to the Nutritional Risk Screening (NRS) assessment.
• Severe food allergy that prevents the subject from consuming the foods required for the fasting-mimicking diet (FMD).
• Symptomatic central nervous system (CNS) metastases, leptomeningeal metastases, or spinal cord compression due to metastases prior to the first dose of study treatment. Exception: Patients with symptomatic CNS metastases who have received treatment and are stable for ≥4 weeks (stable defined as no radiographic progression and resolution of metastasis-related symptoms) and have discontinued systemic corticosteroids (any dose), anticonvulsants, and mannitol for >2 weeks may be enrolled.
• History of other malignancies within 5 years prior to signing the informed consent form (except for cured basal cell skin carcinoma, papillary thyroid carcinoma, etc.).
• Active autoimmune disease requiring systemic treatment (e.g., corticosteroids or immunosuppressants) within the past 2 years prior to the first dose of the combination therapy.
• Any serious concomitant disease, as judged by the investigator, that may endanger the subject's safety or interfere with the subject's ability to complete the study.
• Receiving long-term systemic corticosteroid therapy (daily dose >10 mg prednisone equivalent) within 7 days prior to the first dose of the combination therapy.
• Any of the following cardiovascular diseases:

Acute myocardial infarction within 6 months prior to the first dose of the combination therapy.

History of and/or current New York Heart Association (NYHA) Class III or IV heart failure.

Poorly controlled cardiovascular disease, including angina, pulmonary hypertension, or severe cardiac rhythm or conduction abnormalities.

Mean QT interval corrected by Fridericia's formula (QTcF) >450 ms (male) or >470 ms (female) on 12-lead electrocardiogram (ECG) prior to the first dose of the combination therapy.

• Known history of substance abuse of psychotropic medications, alcohol abuse, or drug abuse; or history of definite neurological or psychiatric disorders, including epilepsy, dementia, or hepatic encephalopathy.
• Participation in another clinical study and receipt of other investigational therapy within 4 weeks prior to the first dose of the combination therapy.
• Major surgery within 4 weeks prior to the first dose of the combination therapy (adequate wound healing after major surgery must be clinically assessed).
• Arteriovenous thromboembolic events within 6 months prior to the first dose of the combination therapy, including cerebrovascular accident, history of stroke or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other serious thromboembolic events.
• Any patient, as judged by the investigator, who may increase the risk associated with the study, interfere with the interpretation of study results, or is deemed unsuitable for enrollment by the investigator and/or sponsor.