An Open-label, Investigator-initiated, Single Arm, Exploratory Phase 2 Trial Evaluating the Feasibility and Efficiency of PET/CT Directed Free of Therapy Used for Metastatic and Advanced Renal Cell Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Progression-free survival (PFS) rate
研究概览
简要总结
This phase 2 trial aims to test the feasibility and efficiency of PET/CT-directed treatment interruption strategy in metastatic renal cell carcinoma patients with IMDC favorable/intermediate risk who achieve complete (CMR) or partial metabolic response (PMR) after ≥12 months of first-line PD-1/PD-L1 Immune checkpoint inhibitor (ICI)+ VEGFR-tyrosine kinase inhibitor (TKI) therapy. It helps figure out whether PET/CT can safely direct treatment pause as well as explores a new individualized treatment option based on metabolic imaging for RCC patients.
详细描述
Current first-line therapy for advanced renal cell carcinoma (RCC) combines tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICIs). Although effective, continuous treatment often results in cumulative toxicities, significant financial burdens, and potential overtreatment for patients.
To improve such limitations, intermittent therapy strategies has gained more attention. However, existing approaches are constrained by insufficient induction periods (<12 months) that may compromise treatment depth, and reliance on anatomic CT criteria (RECIST 1.1) which cannot reliably differentiate residual active tumor from treatment-related fibrosis/necrosis. PET/CT quantifies tumor metabolic activity via standardized uptake values (SUV), enabling early molecular-level response assessment per PERCIST 1.0 criteria, thus shows promising prospects.
This trial implements a two-stage screening approach. During the pre-screening period, eligible unresectable/metastatic RCC patients with IMDC low/intermediate risk sign the Pre-screening Consent Form to receive ≥12 months of standard ICI+TKI therapy. Consolidative surgery and consolidative radiotherapy during combination therapy are permitted. Patients achieving complete metabolic response (CMR) or partial metabolic response (PMR) on PET/CT within 24 months undergo main screening. Those qualifying sign the Informed Consent Form (ICF), discontinue both agents and enter a closely monitored treatment holiday. During this phase, serial imaging (CT with supplemental PET/CT when indicated) will be performed every 12 ± 1 weeks. Therapy will be restarted immediately if any of the following occur:
- A ≥10% increase in the sum of the longest diameters (SLD) of target lesions from nadir, concurrent with a ≥30% increase in the peak standardized uptake value normalized to lean body mass (SULpeak) relative to baseline;
- New lesion with SULpeak exceeding liver background.
Peripheral blood and other biological samples from participants at different time points during the trial will be collected for future analyses. The primary endpoint is progression-free survival (PFS) rate at 24 months from treatment initiation. Secondary endpoints include duration of response after interruption, objective response rate after restarting therapy, safety (CTCAE v5.0-graded adverse events), patient-reported outcomes and cost-effectiveness. This study pioneers metabolic imaging to guide intermittent therapy in mRCC patients, utilizing extended induction and dual anatomic/metabolic restart thresholds to optimize risk-benefit balance while reducing treatment burden.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female subjects aged ≥ 18 years at time of signing informed consent
- •Locally advanced (not amenable to curative surgery or radiation therapy) or metastatic RCC (American Joint Committee on Cancer [AJCC] Stage IV)
- •Favorable or intermediate risk as per International Metastatic RCC Database Consortium (IMDC) criteria
- •Eastern Cooperative Oncology Group performance status 0 or 1
- •Karnofsky Performance Status (KPS) grade ≥ 70%
- •Adequate organ and bone marrow function meeting all laboratory criteria:
- •Ⅰ. Absolute neutrophil count (ANC) ≥ 1.5 × 10³/μL (≥ 1.5 GI/L); Platelet count ≥ 100 × 10³/μL (≥ 100 GI/L); Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
- •Ⅱ. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × upper limit of normal. Total bilirubin ≤ 1.5 × the upper limit of normal (≤ 3 mg/dL [≤ 51.3 μmol/L] if Gilbert's syndrome)
- •Ⅲ. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min using the Cockroft-Gault formula.
- •Capacity to comprehend and comply with protocol requirements, with documented informed consent signed
- •Contraception agreement for sexually active fertile participants and partners to use of medically accepted methods during study and continue for 5 months after last treatment
- •Negative pregnancy status at screening for women of childbearing potential
- •Pre-screening
排除标准
- •Highly malignant pathology
- •Prior systemic therapy for advanced RCC
- •Poor risk as per International Metastatic RCC Database Consortium (IMDC) criteria
- •ECOG performance status >1
- •Karnofsky Performance Status (KPS) <70%
- •Inadequate organ and bone marrow function
- •Bulky or symptomatic disease or hepatic metastases
- •Active brain metastases or leptomeningeal disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before the start of treatment.
- •Concurrent or prior invasive malignancies that could confound efficacy assessment, except adequately treated non-melanoma skin cancer, superficial bladder cancer or carcinoma in situ of the cervix/breast with curative therapy >3 years ago.
- •Uncontrolled hypertension (>150/100 mmHg despite optimal therapy)
- •Uncontrolled comorbidities within 6 months including but not limited to: clinically significant cardiovascular disorders, gastrointestinal disorders with high risk of perforation or fistula formation, significant hematuria, hematemesis, hemoptysis, or major bleeding history, severe infections, severe autoimmune diseases (e.g., systemic lupus erythematosus, immune pneumonitis), active HIV, HBV, or HCV infections.
- •Major surgery within 4 weeks with unhealed wounds or planned surgery during study
- •Concomitant use of drugs or substances affecting activity or pharmacokinetics of investigational products
- •Hypersensitivity to any component of study drugs
- •Chronic or concurrent immunosuppressive therapy, except Inhaled/topical steroids
- •Medical/psychiatric/social conditions compromising protocol compliance
- •Pregnancy, lactation, or refusal of contraception during and for 5 months post-treatment
- •Inability to undergo PET/CT or oral drug administration
- •Main-screening Inclusion Criteria:
- •Patient must receive≥12 months of first line treatment with the combination of PD-1/PD-L1 ICI and VEGFR-TKI, and have not experienced a toxicity that prevents them from continuing on therapy.
- •Patients must achieve complete metabolic response (CMR) or partial metabolic response (PMR) on PET/CT within 24 months of the combination treatment with PD-1/PD-L1 ICI and VEGFR-TKI.
- •Favorable or intermediate risk as per International Metastatic RCC Database Consortium (IMDC) criteria
- •Eastern Cooperative Oncology Group performance status 0 or 1
- •Karnofsky Performance Status (KPS) grade ≥ 70%
- •Adequate organ and bone marrow function meeting all laboratory criteria:
- •Ⅰ. Absolute neutrophil count (ANC) ≥ 1.5 × 10³/μL (≥ 1.5 GI/L); Platelet count ≥ 100 × 10³/μL (≥ 100 GI/L); Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
- •Ⅱ. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × upper limit of normal. Total bilirubin ≤ 1.5 × the upper limit of normal (≤ 3 mg/dL [≤ 51.3 μmol/L] if Gilbert's syndrome)
- •Ⅲ. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min using the Cockroft-Gault formula.
- •Capacity to comprehend and comply with protocol requirements, with documented informed consent signed
- •Contraception agreement for sexually active fertile participants and partners to use of medically accepted methods during study and continue for 5 months after last treatment
- •Negative pregnancy status at screening for women of childbearing potential
- •Main-screening Exclusion Criteria:
- •Failure to complete ≥12 months of first-line PD-1/PD-L1 + VEGFR-TKI therapy due to unmanageable toxicity or other reasons
- •Failure to achieve CMR or PMR on PET/CT within 24 months after combination therapy; new metastatic lesions or disease progression on PET/CT.
- •Poor risk as per International Metastatic RCC Database Consortium (IMDC) criteria
- •ECOG performance status >1
- •Karnofsky Performance Status (KPS) <70%
- •Inadequate organ and bone marrow function
- •Uncontrolled hypertension (>150/100 mmHg despite optimal therapy)
- •Uncontrolled comorbidities including but not limited to: clinically significant cardiovascular disorders, gastrointestinal disorders with high risk of perforation or fistula formation, significant hematuria, hematemesis, hemoptysis, or major bleeding history, severe infections, severe autoimmune diseases (e.g., systemic lupus erythematosus, immune pneumonitis), active HIV, HBV, or HCV infections.
- •Medical/psychiatric/social conditions compromising protocol compliance
- •Pregnancy, lactation, or refusal of contraception during study period.
- •Inability to undergo PET/CT or oral drug administration
- •Withdrawal Criteria:
- •Disease progression with unsatisfactory efficacy, or occurrence of intercurrent illnesses during treatment or follow-up period.
- •Occurrence of severe treatment-related adverse reactions.
- •Laboratory test results indicating critical safety values.
- •Voluntary withdrawal of informed consent by the patient.
- •Investigator's judgment that withdrawal is in the subject's best interest.
- •Pregnancy during the trial period.
- 另有 3 项未显示
研究组 & 干预措施
Treatment pause
Patients achieving complete metabolic response (CMR) or partial metabolic response (PMR) on PET/CT within 24 months discontinue combination regimens with the possibility to restart initial treatment at progression.
干预措施: Intermittent PD-1/PD-L1 ICI + VEGFR-TKI (Drug)
结局指标
主要结局
Progression-free survival (PFS) rate
时间窗: 24 months from treatment initiation
Proportion of participants alive and without disease progression at 24 months will be assessed according to PERCIST 1.0 criteria.
次要结局
- Duration of response (DoR)(From treatment interruption until disease progression or death, assessed up to 24 months)
- Overall survival (OS)(From treatment initiation until death from any cause, assessed up to 5 years)
- Progression free survival (PFS)(From treatment initiation until disease progression or death from any cause, assessed up to 5 years)
- Overall safety profile(From the date of the first study drugs administration up to 90 days after the last dose of study drugs administration)
- Patient-reported outcome (PRO) - Health-related quality of life measured by NCCN FKSI-19(24 months from treatment initiation)
- Patient-reported outcome (PRO) - Health-related quality of life measured by EORTC QLQ-C30(24 months from treatment initiation)
- Patient-reported outcome (PRO) - General Health status measured by EQ-5D-5L(24 months from treatment initiation)
- Patient-reported outcome (PRO) - Anxiety and depression status measured by HADS(24 months from treatment initiation)
- Quality-adjusted life years (QALYs)(24 months from treatment initiation)
- Cost-effectiveness(24 months from treatment initiation)
- Distribution of treatment modality after progression(36 months from treatment initiation)
- Objective response rate (ORR) after restarting treatment(6 months after restarting therapy)
研究者
Le Qu
Associate chief urologist
Jinling Hospital, China