Metastatic Clear Cell Renal Cell Carcinoma
Conditions
Keywords
Metastatic Clear Cell Renal Cell Carcinoma, CD70-Targeted Immuno-PET/CT, Treatment Holiday
Brief summary
The purpose of this study is to evaluate the safety and feasibility of a treatment holiday strategy directed by CD70-targeted immuno-PET/CT in patients with metastatic clear cell renal cell carcinoma (mccRCC). Specifically, the study aims to assess whether patients who achieve both anatomical disease control and metabolic response after 12 months of first-line PD-1/PD-L1 ICI + VEGFR-TKI combination therapy can safely pause their treatment, improve quality of life without compromising therapeutic efficacy.
Detailed description
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. While intermittent therapy shows promise in maintaining efficacy while mitigating adverse events, conventional CT relies on morphological changes and lacks the sensitivity to distinguish viable tumor tissue from post-treatment fibrosis or necrosis, hindering precise decision-making for treatment cessation. CD70 is a transmembrane protein highly expressed in over 80% of mccRCCs. CD70-targeted immuno-PET/CT, utilizing specific single-domain antibodies, provides a superior molecular imaging tool outperforming FDG-PET and allows for accurate assessment of treatment response to guide intermittent therapy. In this multi-center, single-arm, phase II trial, mccRCC patients with IMDC favorable or intermediate risk will be enrolled to receive standard first-line ICI plus TKI combination therapy for 12 months (± 1 months) in the absence of disease progression or unacceptable toxicity. After that, patients will be evaluated using both CT (RECIST 1.1) and CD70 immuno-PET/CT (PERCIST criteria). Patients achieving sustained disease control on CT combined with Complete Metabolic Response (CMR) or Partial Metabolic Response (PMR) on CD70 immuno-PET/CT will qualify to pause all systemic treatments and enter treatment holiday. A per-lesion evaluation principle will be applied for baseline heterogeneous lesions. Patients fail to achieve the predefined criteria will continue first-line systemic therapy until disease progression or unacceptable toxicity. During the treatment holiday, patients will undergo anatomical and molecular monitoring including CT scans every 8-12 weeks and CD70 immuno-PET/CT every 24 weeks. Circulating KIM-1 levels will be longitudinally assessed as an early-warning biomarker. A confirmed clinically meaningful elevation (e.g., ≥ 30% from nadir) may trigger unscheduled or more frequent radiographic evaluations. Original regimen will be immediately restarted upon the occurrence of anatomical progression (RECIST 1.1), metabolic flare (PERCIST), or clinical symptom deterioration. Peripheral blood, other biological samples, and health-related quality of life questionnaires will be collected at different time points during the trial for future analyses.This study aims to establish a multidimensional decision-making framework to optimize the balance between survival benefits and quality of life in advanced RCC.
Interventions
DRUGPD-1/PD-L1 ICI + VEGFR-TKI
All participants will receive first-line PD-1/PD-L1 inhibitor + VEGFR-TKI combination therapy for 12 months (±1 month).
OTHERTreatment pause
Patients who achieve the predefined criteria after 12 months of treatment will discontinue both drugs and enter a closely monitored treatment holiday. Upon radiographic or clinical progression, the previous systemic therapy will be reintroduced according to the protocol and investigator's discretion.
Sponsors
Jinling Hospital, China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
STEP0: At Treatment Initiation 1. Male or female subjects aged ≥ 18 years 2. Locally advanced (not amenable to curative surgery or radiation therapy) or metastatic RCC (American Joint Committee on Cancer \[AJCC\] Stage IV) 3. Histologically or cytologically confirmed advanced RCC with predominantly clear-cell subtype 4. Favorable or intermediate risk as per International Metastatic RCC Database Consortium (IMDC) criteria 5. Karnofsky Performance Status (KPS) grade ≥ 70% 6. At least one measurable lesion on CT per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 7. At least one high-uptake target lesion on CD70-targeted immuno-PET/CT per Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) version 1.0 8. If CD70-negative lesions (visible on CT but lacking CD70 avidity on PET/CT) are present at baseline, they must meet ALL the following conditions: cannot be target lesions, cannot be located in major involved organs, must be ≤ 3 in number, and must account for ≤ 30% of the total tumor burden 9. Adequate organ and bone marrow function meeting all laboratory criteria: * Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L; Platelet count ≥ 100 × 10\^9/L; Hemoglobin ≥90 g/L * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 × upper limit of normal(ULN) (or ≤ 5 × ULN if hepatic metastases are present). Total bilirubin ≤ 1.5 × ULN (≤ 3 mg/dL if Gilbert's syndrome) * Serum creatinine ≤ 2.0 × ULN or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min using the Cockcroft-Gault formula 10. Capacity to comprehend and comply with protocol requirements, with documented informed consent signed 11. Contraception agreement for sexually active fertile participants and partners to use medically accepted methods during the study and continue for 5 months after last treatment 12. Negative pregnancy status at screening for women of childbearing potential STEP1: At 12-Month Evaluation 1. Patient met all eligibility criteria outlined above 2. Patient must receive 12 months (±1m) of first line PD-1/PD-L1 ICI + VEGFR-TKI therapy, without permanent discontinuation of both agents due to unmanageable toxicity 3. Patient must have completed an CD70-targeted immuno-PET/CT scan at 12m (±1m) from start of initial therapy 4. Patients must meet one of the following criteria: * Eligible for treatment discontinuation: For CD70-Positive Lesions: Sustained Disease Control (Complete Response \[CR\], Partial Response \[PR\], or Stable Disease \[SD\]) on CT for ≥ 12 weeks per RECIST 1.1, AND achieved Complete Metabolic Response (CMR) or Partial Metabolic Response (PMR) on CD70 immuno-PET/CT per PERCIST 1.0 criteria; For CD70-Negative Lesions (If present at baseline): Must achieve a deep anatomical response, defined as Complete Response (CR) or Partial Response (PR) on CT, maintained for ≥ 12 weeks per RECIST 1.1 * Treatment continuation: not meeting criteria above
Exclusion criteria
STEP0: At Treatment Initiation 1. Prior systemic therapy for advanced RCC 2. Poor risk as per International Metastatic RCC Database Consortium (IMDC) criteria 3. Karnofsky Performance Status (KPS) \<70% 4. Inadequate organ and bone marrow function 5. Active brain metastases or leptomeningeal disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) who are clinically stable without progression prior to treatment 6. Concurrent or prior invasive malignancies within the past 5 years, except adequately treated in situ/superficial cancers (e.g., non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix/breast) 7. Presence of uncontrolled major comorbidities or recent severe illnesses within 6 months, including but not limited to: uncontrolled hypertension, clinically significant cardiovascular disease, GI disorders with high risk of perforation/fistula, significant hematuria, hematemesis, hemoptysis, major bleeding history, severe active infections (including active HIV, HBV, or HCV), or severe autoimmune diseases (e.g., systemic lupus erythematosus, immune pneumonitis) 8. Life expectancy \< 6 months 9. Known allergy or hypersensitivity to the CD70 imaging agent or any of its excipients 10. Severe hepatic or renal insufficiency, or inability to tolerate PET/CT examination 11. Medical/psychiatric/social conditions compromising protocol compliance 12. Pregnancy, lactation, or refusal of contraception during and for 5 months post-treatment STEP1: At 12-Month Evaluation 1. Failure to complete 12 months(±1m) of first-line PD-1/PD-L1 + VEGFR-TKI therapy due to unmanageable toxicity or disease progression 2. Failure or inability to undergo CD70-targeted immuno-PET/CT scan at the 12-month evaluation timepoint 3. Unacceptable clinical deterioration or investigator discretion indicating that a treatment holiday is not in the best interest of the patient
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-free survival (TFS) rate | 12 months after treatment discontinuation | Defined as the proportion of patients who are alive without having restarted the original therapy at 12 months following discontinuation of the combination therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | From treatment initiation until 3 years of follow-up | Time from enrollment to date of death due to any cause. |
| Progression free survival (PFS) | From treatment initiation until 3 years of follow-up | Time from enrollment to first documented disease progression or death, whichever occurs first. |
| Overall safety profile | From treatment initiation until 3 years of follow-up | Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 criteria. |
| Patient-reported outcome (PRO) - Health-related quality of life measured by NCCN FKSI-19 | From treatment initiation until 2 years of follow-up | Measured by the NCCN functional assessment of cancer therapy-kidney symptom index (FKSI-19), a 19-item scale assessing treatment-related symptoms and side effects for kidney cancer patients. |
| Patient-reported outcome (PRO) - Health-related quality of life measured by EORTC QLQ-C30 | From treatment initiation until 2 years of follow-up | Measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), a 30-item instrument assessing various domains of physical, emotional, and social functioning for cancer patients. |
| Patient-reported outcome (PRO) - General Health status measured by EQ-5D-5L | From treatment initiation until 2 years of follow-up | Measured by the "5-Level EuroQol Group's 5-Dimension" (EQ-5D-5L) questionnaire which comprises the EQ-5D index evaluating health across five dimensions and the EQ-VAS which is a 0-100 visual scale for self-rated overall health. |
| Patient-reported outcome (PRO) - Anxiety and depression status measured by HADS | From treatment initiation until 2 years of follow-up | Measured by the Hospital Anxiety and Depression Scale (HADS) which contains 14 items with 7 items measuring anxiety level and 7 items measuring depression level. |
| Quality-adjusted life years (QALYs) | From treatment initiation until 2 years of follow-up | The quality-adjusted time without symptoms or toxicity (Q-TWiST) integrates data from patient-reported outcomes (PROs) into survival calculations. It quantifies the utility-weighted sum of mean time across three health states: time with all-cause grade 3/4 toxicity prior to progression, time without grade 3/4 toxicity or symptoms of progression, and time after progression. |
| Cost-effectiveness | From treatment initiation until 2 years of follow-up | Measured by the incremental cost-effectiveness ratio (ICER) to provide the ratio of incremental cost per additional quality-adjusted life year (QALY). |
| Duration of response (DoR) | From treatment discontinuation until 2 years of follow-up | Time from first documented complete metabolic response (CMR) or partial metabolic response (PMR) to progression or death. |
| Distribution of treatment modality after progression | From treatment discontinuation until 2 years of follow-up | Proportion of participants receiving surveillance, focal treatment, or systemic therapy after disease progression. |
| Objective response rate (ORR) after restarting treatment | From treatment discontinuation until 2 years of follow-up | Proportion of participants achieving objective response within 6 months of restarting therapy after progression. |
| Time to subsequent therapy initiation | From treatment discontinuation until 2 years of follow-up | Time from treatment discontinuation to the start of subsequent systemic therapy or death, whichever occurs first. |
Countries
China
Contacts
CONTACTLe Qu, Ph.D.
PRINCIPAL_INVESTIGATORLe Qu, Ph.D.
Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University
Outcome results
None listed