Gut Microbiota Modulation for Immunotherapy Resensitization in Advanced Renal Cell Carcinoma

Summary

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.

Conditions

• Advanced RCC

Interventions

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.

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.

Sponsors & Collaborators

• Jinling Hospital, China

  lead OTHER

Principal Investigators

• Le Qu, Ph.D. · Jinling Hospital, China

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

90 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-06-01

Primary Completion

2028-12-31

Completion

2028-12-31

Countries

• China

Study Locations