This is a single-arm phase II clinical trial to evaluate the initial efficacy and safety of
Sintilimab, a PD-1 Inhibitor, as Second-line Treatment in FH-deficient Renal Cell Carcinoma.
Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare subtype of RCC
characterized by germline/somatic mutation of the fumarate hydratase (FH) gene, and is an
extremely aggressive tumor, with a propensity to disseminate early even in the setting of a
small primary tumor.
Loss-of-function mutation of FH results in the accumulation of fumarate, impairment of
oxidative phosphorylation, alteration of the metabolic state, and stabilization of
hypoxia-inducible factor (HIF)-1α, thus activating angiogenic and oxidative stress response
pathways. Unlike the robust response of clear cell RCC (ccRCC) to antiangiogenic agents,
blocking the antiangiogenic pathway does not lead to better outcomes in FH-deficient RCC.
Anti-mTOR agents are also ineffective.
Although the National Comprehensive Cancer Network (NCCN) guideline recommends the
combination of bevacizumab plus erlotinib or everolimus for metastatic FH-deficient RCC,
high-level evidence for standardized systematic therapy remains scarce.
In the present study, the investigators plan to assess the efficacy and safety of
immunotherapy with Sintilimab as second-line treatment in FH-deficient RCC, and to explore
potential biomarkers related to the treatment efficacy by means of detection, including but
not limited to the next-generation sequencing, flow cytometry, etc.
Inclusion Criteria:
1. ≥18 years old;
2. histopathological evidence of FH-deficient renal cell carcinoma, which was confirmed
by Sanger or next-generation sequencing after initial screening by IHC.
3. included patients must be diagnosed with metastatic renal cell carcinoma or have a TNM
stage IV (according to 2009 TNM Classification). Patients must have received treatment
of targeted agents or immunotherapy (including cytokine therapy) before enrollment.
4. ECOG score ≤2;
5. life expectancy ≥ 3 months;
6. sign informed consent, and be able to follow the visit and related procedures
stipulated in the program;
7. agree to collect tumor tissue, blood and other specimens required by this study and
apply them to relevant studies;
8. important organs and bone marrow functions meet the following requirements: absolute
neutrophil count (ANC) ≥1.5×109/L, platelet (PLT) ≥100×109/L, hemoglobin (HGB)
≥9g/dL;Liver function: serum total bilirubin (TBIL) ≤1.5 times normal upper limit
(ULN), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤2.5
times ULN, serum albumin (ALB) ≥ 2.8g /dL. Renal function: serum creatinine (Cr)
≤1.5×ULN, or creatinine clearance ≥40 mL/min
Exclusion Criteria:
1. patients with other malignant tumors with different primary sites or histology from
the tumor evaluated in this study within 2 years of personal history, except those
with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or cervical
carcinoma in situ under good control;
2. major surgery or severe trauma within 4 weeks before enrollment;
3. immunosuppressive drugs were used within 4 weeks prior to the first dose of study
therapy, excluding local glucocorticoids, inhaled or otherwise, or systemic
glucocorticoids at physiological doses (i.e., no more than 10mg/ d prednisone or
equivalent doses of other glucocorticoids);
4. known or suspected active autoimmune diseases (congenital or acquired), such as
interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation,
vasculitis, nephritis, thyroiditis, etc. Patients with type 1 diabetes with good
insulin control can also be enrolled.
5. known allogeneic organ transplantation (except corneal transplantation) or allogeneic
hematopoietic stem cell transplantation;
6. allergic to any component of monoclonal antibody;
7. suffering from other uncontrolled serious diseases, including but not limited to: A)
severe infection in the active phase or clinically poorly controlled; B) HIV infection
(HIV antibody positive); C) acute or chronic active hepatitis b (HBsAg positive and
HBV DNA>1*103/ml) or acute or chronic active hepatitis c (HCV antibody positive and
HCV RNA>15IU/ml); D) active tuberculosis, etc.;
8. class iii-iv congestive heart failure (New York heart association classification),
poorly controlled and clinically significant arrhythmia;
9. uncontrolled arterial hypertension (systolic blood pressure ≥160mmHg or diastolic
blood pressure ≥100mmHg);
10. had any arterial thrombosis, embolism or ischemia, such as myocardial infarction,
unstable angina, cerebrovascular accident or transient ischemic attack, etc. within 6
months before the selected treatment;
11. diseases requiring the use of warfarin (coumarin) for anticoagulant treatment;
12. uncontrolled hypercalcemia (more than 1.5 mmol/L of calcium or calcium greater than 12
mg/dL or adjusted serum calcium greater than ULN), or symptomatic hypercalcemia
requiring continued bisphosphate treatment;
13. accompanied by other malignant tumors (except those that have been cured, such as
cervical carcinoma in situ, non-melanoma skin cancer, etc.);
14. other acute or chronic diseases, psychiatric disorders, or laboratory abnormalities
that may result in increased risk associated with study participation or study drug
administration, or interference with the interpretation of study results, and
ineligibility to participate in the study as determined by the investigator;
15. pregnant or lactating women.
