Gut Microbiota Modulation for Immunotherapy Resensitization in Advanced Renal Cell Carcinoma (REMEDY-RCC)

REMEDY-RCC: Gut Microbiota Modulation for Immunotherapy Resensitization in Advanced Renal Cell Carcinoma - A Prospective, Exploratory, Single-Center Study

The combination of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) has significantly improved clinical outcomes in patients with advanced renal cell carcinoma (RCC). However, 40%-60% of patients still develop primary or acquired resistance. For those with resistant disease, current immune rechallenge strategies have yet to demonstrate clear clinical benefit. Emerging evidence indicates that the gut microbiota plays a critical role in modulating responses to immunotherapy. Microbiota-modulating approaches, including fecal microbiota transplantation (FMT) and live bacterial formulations such as CBM588, have shown preliminary potential to enhance sensitivity to immunotherapy and improve patient outcomes. Nevertheless, whether gut microbiota modulation can resensitize advanced RCC to immunotherapy remains to be investigated.

The REMEDY-RCC trial is an investigator-initiated, prospective, open-label, phase II, parallel two-cohort exploratory study primarily designed to investigate whether gut microbiota modulation can restore sensitivity to immunotherapy in patients with advanced RCC. Given the substantial differences in the tumor immune microenvironment and response to ICIs between clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC), this study employs a parallel two-cohort design to stratify these two patient populations: a primary cohort consisting of patients with metastatic ccRCC, and an exploratory cohort consisting of patients with metastatic nccRCC. The primary and secondary endpoints will be analyzed in the primary cohort, whereas the exploratory cohort will be used solely for exploratory and descriptive analyses. The study plans to enroll approximately 33 adult patients with advanced or metastatic RCC, including 27 with metastatic ccRCC and 6 with metastatic nccRCC. Eligible patients will receive the following sequential interventions: bowel decontamination with amoxicillin-clavulanate potassium followed by polyethylene glycol (PEG) solution, high-dose gut colonization and maintenance supplementation with live Clostridium butyricum powder combined with soluble dietary fiber, and immune rechallenge therapy consisting of a PD-1 immune checkpoint inhibitor (ICI) combined with four cycles of a CTLA-4 ICI, followed by maintenance therapy with the PD-1 ICI alone. Treatment will continue until disease progression, unacceptable toxicity, completion of the planned treatment cycles, or withdrawal of consent.

The REMEDY-RCC trial requires specific follow-up for enrolled patients. Radiological response is assessed longitudinally using computed tomography (CT). Tissue and body fluid samples collected from patients will be used for biomarker and multi-omic analyses.

The primary endpoint of the trial is the objective response rate (ORR) in the primary cohort, as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Sample size for the primary cohort was determined using Simon's optimal two-stage design, with a one-sided α of 0.10 and power (1-β) of 0.80. The unacceptable response rate (P0) was set at 17.4%, based on the ORR observed in the FRACTION-RCC study for nivolumab plus ipilimumab rechallenge in patients with metastatic ccRCC who had progressed after prior immunotherapy. The target response rate (P1) was established considering that FMT has been shown to increase ORR by approximately 20% in immunotherapy-resistant melanoma. Given that metastatic RCC and melanoma are both considered immunologically responsive tumor types, a comparable therapeutic benefit from gut microbiota remodeling is anticipated. Accordingly, P1 was set at 37.4%. This effect size is clinically meaningful and would be non-inferior to the clinical efficacy of cabozantinib in metastatic RCC that has progressed following immunotherapy.

The primary cohort will initially enroll six patients for safety assessment. If the treatment is deemed safe, further accrual will follow Simon's two-stage design, and enrollment of the exploratory cohort will be considered. After these six patients, an additional six patients will be enrolled, bringing the total to 12, at which point an interim analysis will be performed. If the number of objective responses at the interim analysis is ≤ 2, the trial will be terminated early. If ≥3 objective responses are observed, an additional 12 patients will be enrolled, resulting in a total sample size of 24 patients. Accounting for a potential 10% dropout rate, the study plans to enroll 27 patients in total.

The exploratory cohort is planned to enroll no more than 6 patients (not exceeding 20% of the total enrollment), with a fixed-sample descriptive design. The sample size calculation is not based on statistical hypothesis testing, and all efficacy endpoints will be reported using descriptive statistics. The total planned sample size is 33 patients, comprising 27 patients in the primary cohort and 6 patients in the exploratory cohort.

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced RCC
• Intervention / Treatment: Drug: Toripalimab; Drug: Ipilimumab

• Study Type: Interventional
• Enrollment (Estimated): 33
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Le Qu, Ph.D.; Phone Number: +86 15720625951; Email: septsoul@hotmail.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University
      • Contact: Le Qu, Ph.D.; Phone Number: +86 15720625952; Email: septsoul@hotmail.com
      • Contact: Shaochuan Chen; Email: chensc4556@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pathological Diagnosis and Subtype Specification Histologically confirmed metastatic renal cell carcinoma (mRCC) of either clear cell type or non-clear cell type, with non-clear cell histologies restricted to papillary, chromophobe, or unclassified subtypes. Sarcomatoid features are allowed. Other non-clear cell subtypes, including but not limited to collecting duct carcinoma and renal medullary carcinoma, are excluded.

Based on the pathological subtype, enrolled patients will be assigned to two cohorts: the primary cohort consists of patients with histologically confirmed metastatic clear cell RCC, and the exploratory cohort consists of those with histologically confirmed metastatic non-clear cell RCC (subtypes limited to papillary, chromophobe, or unclassified).

• Immunotherapy Resistance Patients must have received at least two cycles of PD-1/PD-L1 ICI therapy and demonstrated disease progression either during treatment or within six months after the last dose. Progressive disease must be confirmed by the investigator according to RECIST 1.1 criteria, with additional radiographic confirmation performed within four weeks after the initial documented progression.
• Prior Treatment Lines and Sequence Restriction Patients must have received no more than two prior lines of systemic therapy, with no more than one line consisting of a PD-1/PD-L1 ICI. This PD-1/PD-L1 ICI based therapy may have been administered as first-line or second-line treatment for advanced or metastatic RCC, or as neoadjuvant or adjuvant therapy. Furthermore, this line of therapy must be the most recent prior treatment line, meaning that no other anticancer therapy has been administered following its completion.
• Lesion Requirement Patients must have at least one measurable lesion per RECIST v1.1, as assessed by the investigator or by local radiologic evaluation.
• Pre-treatment Tumor Biopsy Quality The pre-treatment tumor biopsy specimen must contain viable tumor tissue accounting for at least 75% of the total examined area.
• Prior Radiotherapy Washout Participants who have received palliative radiotherapy for non-central nervous system lesions must complete such therapy at least 2 weeks prior to the first dose of study treatment. Participants for whom the only measurable lesions reside within a previously irradiated field are eligible for enrollment, provided that such lesions have shown clear progression and remain accurately measurable.
• Recovery from Prior Treatment Toxicity All toxicities from prior anticancer therapies must have recovered to baseline or to Grade ≤1 according to the CTCAE version 5.0, with the exception of controllable AEs such as hypothyroidism that are clinically insignificant or remain stable under supportive care.
• General Baseline Status Patients must be ≥18 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status <2, an American Society of Anesthesiologists (ASA) score ≤2, and a life expectancy ≥6 months.
• Adequate Liver Function Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤3 × upper limit of normal (ULN), or ≤5 × ULN in patients with liver metastases. Total bilirubin ≤1.5 × ULN, except for patients with Gilbert's syndrome, in whom bilirubin ≤3.0 mg/dL is allowed.
• Adequate Renal Function Creatinine clearance ≥30 mL/min (Cockcroft-Gault formula) or serum creatinine ≤1.5 × ULN, and urine protein-to-creatinine ratio ≤1 mg/mg.
• Adequate Bone Marrow Function White blood cell count >2.0 × 10⁹/L, absolute neutrophil count >1.5 × 10⁹/L, platelet count >100 × 10⁹/L, lymphocyte count ≥0.3 × 10⁹/L, and hemoglobin ≥90 g/L, with no blood transfusion within 14 days prior to assessment.
• Viral Serology Patients must be negative for human immunodeficiency virus (HIV), negative for hepatitis B surface antigen (HBsAg), or positive for hepatitis B core antibody (HBcAb) with negative HBV DNA, and negative for hepatitis C antibody (HCV Ab), or positive with negative HCV RNA.
• Informed Consent Patients must provide written informed consent.
• Compliance Patients must be willing and able to adhere to the study protocol.

Exclusion Criteria:

- Recent Microbiota Interference Patients are excluded if they have received systemic antibiotics within 4 weeks prior to screening, or have received any live bacterial preparations or commercial prebiotics within 2 weeks prior to screening, or are currently using or plan to use probiotics, yogurt, or foods supplemented with bacteria during the treatment period.

- Immune-Related Severe Toxicity or Autoimmune Status

Patients are excluded if they meet any of the following criteria:

• Have a history of permanent discontinuation of immunotherapy due to immune-mediated adverse events;

  • Have active or known autoimmune disease, except for type 1 diabetes mellitus, hypothyroidism requiring only hormone replacement therapy, and vitiligo;

    • Have an immunosuppressive status, defined as confirmed immunodeficiency, receipt of systemic corticosteroids at a dose equivalent to >10 mg of prednisone per day or other immunosuppressive agents (excluding inhaled or topical corticosteroids), or a history of active autoimmune disease requiring systemic therapy within the past 2 years.

      - Prior Specific Immunotherapy or Excessive Therapy Patients are excluded if they have received prior treatment with a CTLA-4 ICI or more than two prior systemic therapy regimens.

      - Gastrointestinal Risk Factors Patients are excluded if they have a history of inflammatory bowel disease (including Crohn's disease or ulcerative colitis); chronic severe diarrhea; or grade ≥3 immune-related colitis; or present with gastrointestinal metastatic lesions; or have undergone major abdominal surgery that may impair intestinal absorption or peristaltic function.

      - Oral Administration Barrier Patients are excluded if they have dysphagia or are unable to take the required oral study medication.

      - Rapid Tumor Progression Patients are excluded if they have rapidly progressive disease such that, in the opinion of the investigator, they cannot safely tolerate a 4-week washout period and a 2-week reconditioning period.

      - Active Interstitial Lung Disease or Pneumonitis Patients with active interstitial lung disease or pneumonitis, or a history of either condition requiring systemic steroid therapy, are excluded.

      - Uncontrolled Brain Metastases or Central Nervous System Disease Patients with known brain metastases, cranial epidural disease, or significant vasogenic edema are excluded unless they have received adequate radiotherapy or surgery and have been stable for at least 4 weeks prior to the first dose of study treatment.

      - Severe Cardiac Disease Patients are excluded if they have a history of myocarditis or congestive heart failure (New York Heart Association [NYHA] class III-IV), unstable angina, uncontrolled severe arrhythmia, or myocardial infarction within 6 months prior to enrollment.

      - Recent Other Antineoplastic Treatment Patients are excluded if they have received, prior to the first dose of study treatment:any small molecule kinase inhibitor within 2 weeks; cytotoxic agents, biologics, or other systemic anticancer therapies within 4 weeks; radiotherapy for bone metastases within 2 weeks, or any other radiotherapy within 4 weeks.

      • Planned Other Antineoplastic Treatment Patients are excluded if they require any other systemic or local antineoplastic therapy during the study period, with the exception of bisphosphonates or denosumab for the management of bone metastases.
      • Active Second Malignancy Patients are excluded if they have a second active malignancy diagnosed within the preceding 2 years, with the exception of indolent or early-stage tumors, including non-melanoma skin cancer and carcinoma in situ.
      • Laboratory Abnormalities

Patients are excluded if they meet any of the following criteria:

• White blood cell count <2.0 × 10⁹/L, absolute neutrophil count <1.5 × 10⁹/L, or platelet count <100 × 10⁹/L;

  • AST/ALT >3 × ULN, or >5 × ULN in patients with liver metastases, or total bilirubin >1.5 × ULN (except for Gilbert's syndrome); ③Creatinine clearance <30 mL/min or serum creatinine >1.5 × ULN.

    • Other Uncontrolled Comorbidities

Patients are excluded if they have any of the following:

• Uncontrolled tumor-related pain, with painful lesions requiring palliative radiotherapy to be managed prior to enrollment;

  • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage more frequently than once per month, the presence of an indwelling catheter such as a PleurX® device is permitted; ③Moderate to severe hepatic impairment, defined as Child-Pugh class B or C; ④Uncontrolled or symptomatic hypercalcemia.

    • Other General Exclusions

Patients are excluded if they meet any of the following criteria:

• Have received prior allogeneic stem cell transplantation or solid organ transplantation;

  • Have active hepatitis B (HBV DNA positive), active hepatitis C (HCV RNA positive), or HIV infection;

    • Have undergone major surgery within 4 weeks prior to study treatment;

      • Have a history of allergy to food or antibiotics; ⑤Are pregnant, breastfeeding, or plan to conceive or father children during the study period (from pre-screening or screening visit until 120 days after the last dose); ⑥Require dialysis, have malabsorption syndrome, uncontrolled electrolyte disturbances, or require specific anticoagulants such as warfarin; ⑦Have any medical or psychological condition that may compromise safety or compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Gut Microbiota Modulation Combined with Dual Immunotherapy; Eligible patients first received oral amoxicillin-clavulanate potassium (914mg, BID) for 5 days, followed by a 1-day washout. On day 7, PEG solution (74g, single dose PO) was administered for intestinal decontamination. From day 8 onward, a high-dose regimen of live Clostridium butyricum powder (120mg, BID PO) combined with soluble dietary fiber (5g, BID PO) was given orally for seven days to promote gut colonization. Beginning on day 15, patients received four cycles of toripalimab (240 mg, Q3W) plus ipilimumab (1mg/kg, Q3W) intravenously. During this combination immunotherapy period, subjects continued to take oral live Clostridium butyricum powder (80mg, BID PO) and soluble dietary fiber (10g, BID PO) until the initiation of the fifth immunotherapy cycle. From the fifth cycle onward, patients switched to toripalimab monotherapy (240mg, Q3W) until disease progression, unacceptable toxicity, completion of the prespecified treatment course, or withdrawal from the study.

Drug: Toripalimab; Beginning on day 15, patients receive toripalimab (240 mg, Q3W IV) until disease progression, unacceptable toxicity, completion of the prespecified treatment course, or withdrawal from the study. Dose modifications are as follows: administration of toripalimab may be delayed in patients suspected of experiencing grade 3 or higher adverse events attributable to toripalimab, as per CTCAE version 5.0. In the event of serious adverse reactions, treatment discontinuation is permitted. Investigators may adjust the dosing regimen for patients achieving a complete or partial response, in accordance with the study protocol.; Other Names: anti-PD-1 monoclonal antibody; Drug: Ipilimumab; Patients will receive four cycles of ipilimumab (1mg/kg, Q3W IV). During study treatment, if a patient experiences Grade ≥2 or intolerable adverse events, the investigator may evaluate the patient's condition and resume toripalimab plus ipilimumab therapy after the toxicity has resolved to Grade ≤1 or returned to baseline, with a treatment interruption not exceeding 21 days in principle. Ipilimumab should be discontinued, and the patient should enter the study follow-up phase, if any of the following criteria are met:①Grade ≥3 immune-related adverse events,② symptomatic progression leading both the physician and patient to opt for an alternative treatment, ③patient refusal to continue ipilimumab therapy, or the investigator's judgment that ipilimumab is no longer appropriate for the patient.; Other Names: anti-CTLA-4 monoclonal antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate(ORR)	The efficacy population (EP) comprised patients who received at least one dose of toripalimab plus ipilimumab and had measurable disease at baseline. Tumor responses were assessed by an independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The best overall response was defined as either complete response (CR) or partial response (PR). The primary endpoint was the proportion of patients in the EP achieving CR or PR. All responses required confirmation by repeat imaging performed at least four weeks after the initial documentation.	At week 14 after study initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival（PFS）	PFS was defined as the time from the first treatment date to the first documented disease progression per RECIST version 1.1 as assessed by an IRC, or death from any cause, whichever occurred first. For patients who had not experienced an event by the analysis data cutoff date, data were censored at the date of the last radiological evaluation.	Up to 3 years after treatment
Disease Control Rate（DCR）	Per RECIST version 1.1, the proportion of patients in the EP with a best overall response of CR, PR, or stable disease (SD) was assessed by an IRC. Confirmed responses (CR/PR) required repeat imaging at least 4 weeks after the initial documentation. SD had to be maintained for at least 8 weeks from the first assessment.	At week 14 after study initiation.
Duration of Response（DoR）	Among patients achieving a CR or PR, the DOR was defined as the time from the first documented response (CR or PR) to the first documented disease progression per RECIST v1.1 or death from any cause, whichever occurred first.	Up to 3 years after treatment
Overall Survival（OS）	OS was defined as the time from the first treatment date to death from any cause. Patients who were still alive or lost to follow-up at the analysis data cutoff date were censored at the date of the last known alive status.	Up to 3 years after treatment
Safety and Tolerability	Safety and tolerability were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. The safety analysis set (SAS) comprised all patients who received at least one dose of toripalimab plus ipilimumab. Evaluated parameters included the incidence, severity, and causal relationship to the treatment regimen of treatment-related adverse events (AEs), serious adverse events (SAEs), and immune-related adverse events (irAEs), as well as the proportion of patients with treatment discontinuation, dose delay, or dose adjustment due to adverse events.	From enrollment to 14 weeks after last dose
Patient quality of life - Assessment will be performed using the NCCN FKSI-19+.	The NCCN FKSI-19⁺ is a disease-specific symptom burden scale for patients with renal cell carcinoma. It comprises 19 core items that capture disease-related symptoms, treatment side effects, and functional status, making it suitable for longitudinal clinical monitoring and efficacy evaluation. The assessment time points include: baseline (before treatment), week 6 (with an allowable window of ±7 days), week 12 (with an allowable window of ±7 days), and every 12 weeks thereafter (±7 days) until the end of treatment.	Up to 2 years after treatment
Patient quality of life - Assessment will be performed using the QLQ-C30.	The EORTC QLQ-C30 is a core quality of life questionnaire developed by the European Organisation for Research and Treatment of Cancer. It comprises 30 items that assess five functional domains (physical, role, cognitive, emotional, and social), three symptom domains (fatigue, nausea/vomiting, and pain), global health status, and several single-item symptom measures. It is widely used for the standardized assessment of health-related quality of life in patients with malignant tumors. The assessment time points include: baseline (before treatment), week 6 (with an allowable window of ±7 days), week 12 (with an allowable window of ±7 days), and every 12 weeks thereafter (±7 days) until the end of treatment.	Up to 2 years after treatment
Patient quality of life - Assessment will be performed using the EuroQoL EQ-5D-5L.	The EuroQoL EQ-5D-5L is a preference-based generic health status instrument consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with five severity levels, along with a visual analog scale. It is used to derive health utility values and is applicable for cost-utility analysis and population health surveys. The assessment time points include: baseline (before treatment), week 6 (with an allowable window of ±7 days), week 12 (with an allowable window of ±7 days), and every 12 weeks thereafter (±7 days) until the end of treatment.	Up to 2 years after treatment
Patient quality of life - Assessment will be performed using the HADS.	The Hospital Anxiety and Depression Scale (HADS) comprises 14 items, with seven items each for the anxiety and depression subscales, scored on a four-point scale from 0 to 3. It was designed for use in non-psychiatric hospitalized patients to minimize the interference of somatic symptoms with the assessment of emotional states. The scale demonstrates good clinical feasibility, reliability, and validity. The assessment time points include: baseline (before treatment), week 6 (with an allowable window of ±7 days), week 12 (with an allowable window of ±7 days), and every 12 weeks thereafter (±7 days) until the end of treatment.	Up to 2 years after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate in the Exploratory Cohort	Tumor responses were assessed by an Independent Review Committee according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In the exploratory cohort, among all patients who received at least one dose of toripalimab in combination with ipilimumab and had measurable disease at baseline, the objective response rate was defined as the proportion of patients whose best overall response was either complete response or partial response. All responses required confirmation by repeat imaging performed at least four weeks after the initial documentation. All summarized results for the above endpoints will be described using only descriptive statistics, and are intended to serve as hypothesis-generating evidence for future investigations.	At week 14 after study initiation
Progression-Free Survival in the Exploratory Cohort	Progression-free survival (PFS) was evaluated in the exploratory cohort. PFS was defined as the time from the start of first treatment to the first occurrence of either disease progression confirmed by an Independent Review Committee according to RECIST version 1.1, or death from any cause, whichever occurred first. For patients who had not experienced any of these events by the data cutoff date, their data were censored at the date of the last radiographic assessment. All summarized results for the above endpoints will be described using only descriptive statistics, and are intended to serve as hypothesis-generating evidence for future investigations.	Up to 3 years after treatment
Analysis of Peripheral Blood Samples.	In this study, peripheral blood samples will be collected before, during, and after treatment. Flow cytometry and other techniques will be used to assess dynamic changes in the peripheral immune microenvironment and to explore potential circulating biomarkers.	Up to 1 years after treatment
Analysis of Fecal Samples	In this study, fecal samples will be collected before, during, and after treatment. Metagenomic sequencing together with 16S rRNA gene sequencing will be performed to analyze alterations in gut microbiome diversity over the course of treatment.	Up to 1 years after treatment
Analysis of Tumor Tissue Specimens	Tumor tissue specimens will be obtained before and after treatment to characterize changes in the tumor microenvironment.	At week 14 after study initiation

Collaborators and Investigators

• Sponsor: Jinling Hospital, China
• Investigators: Principal Investigator: Le Qu, Ph.D., Jinling Hospital, China

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: May 11, 2026
• First Submitted That Met QC Criteria: May 20, 2026
• First Posted (Actual): May 28, 2026

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; Advanced Renal Cell Carcinoma; Gut Microbiota Modulation; Resensitization
• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Ipilimumab; toripalimab; spartalizumab
• Other Study ID Numbers: 2026DZKY-087-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No