Efficacy and Safety of Fruquintinib in Combination With Sintilimab in Advanced Renal Cell Carcinoma (FRUSICA-2)

The target populations for this study were patients with histologically or cytologically confirmed, locally advanced/ metastatic renal cell carcinoma who progressed during or after or intolerant to previous first-line VEGFR-TKI therapy.

A total of about 249-264 patients are planned to be enrolled in the study, among whom about 234 patients are planned to be enrolled in the first part. The patients who are successfully enrolled will be randomly assigned into the investigational arm or the control arm in a 1:1 ratio. The enrollment of part 2 will be started after that of part 1 is completed. About 15\~30 patients are planned to be enrolled in the second part. The patients who are successfully enrolled will receive fruquintinib monotherapy.

• fruquintinib+sintilimab (Drug), also known as HMPL-013 + IBI308: fruquintinib, 5 mg, QD, PO, 2 weeks on/1 week off, 3 weeks/cycle; sintilimab, 200 mg, IV infusion, Q3W, 3 weeks/cycle.
• axitinib / everolimus (Drug): axitinib, 5 mg, twice daily (BID), PO, 3 weeks/cycle, dose escalation will be at the investigator 's discretion based on clinical; everolimus, 10 mg, QD, PO, 3 weeks/cycle.
• fruquintinib (Drug), also known as HMPL-013: fruquintinib, 5 mg, QD, PO, 3 weeks on/ 1 week off, 4 weeks/cycle.

Primary outcomes

• Progression free survival (PFS) in Part I [Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months.]: PFS per RECIST 1.1 by BIRC
• Objective response rate (ORR) in Part II [Time from the date of first treatment administration until disease progression or the introduction of a new treatment, assessed up to 20 months.]: ORR per RECIST 1.1 by investigator

Secondary outcomes

• PFS [Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months.]: PFS per RECIST 1.1
• Safety in Part I [Through study completion, assessed up to 20 months.]: Severity and Incidence of Adverse event (AEs) and findings in Laboratory test, vital signs, 12-lead Electrocardiogram (ECG), etc. in Part I
• Quality of life in Part I [Through study completion, assessed up to 20 months.]: Quality of life questionnaire analysis in Part I, the questionnaire include European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). It consists of 30 questions, divided into 15 categories, including 5 functional categories (physical, role, emotional, cognitive, and social), 3 symptom categories (fatigue, pain, nausea and vomiting), 1 overall health status/life quality category, and 6 individual items (each item represents a symptom). For questions 1 to 28, the scores of 1 to 4 correspond to the levels of "none", "a little", "quite", and "very", while for questions 29 and 30, the scores of 1 to 7 correspond to the range from "very bad" to "very good". The scoring rules state that higher scores in the functional categories and overall health status category indicate better functional conditions and life quality, while higher scores in the symptom categories indicate more symptoms or problems (and poorer life quality).
• Quality of life in Part I [Through study completion, assessed up to 20 months.]: Quality of life questionnaire analysis in Part I, the questionnaire include Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-15). It was developed based on 34 symptoms related to kidney cancer, consisting of 15 questions, covering four aspects: symptom signs, respiratory symptoms, quality of life, and emotional symptoms. Each question has a score ranging from 0 to 4, corresponding to "not at all", "a little", "somewhat", "quite", and "very". The higher the score, the milder the symptoms (and the better the quality of life). The total score of the 15 individual questions ranges from 0 to 60.
• Safety in Part II [Through study completion, assessed up to 20 months.]: Severity and incidence of AEs and findings in such as Laboratory test, vital signs, 12-lead ECG, etc. in Part II.
• Disease control rate (DCR) [Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months.]: PFS per RECIST 1.1
• ORR [Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months.]: ORR per RECIST 1.1
• Duration of response (DoR) [Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months.]: DoR per RECIST 1.1
• Time to Response (TTR) [Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months.]: TTR per RECIST 1.1
• OS [Time from date of randomization until the date of death from any cause, assessed up to 20 months.]: OS

Sex: All, ages: 18 Years to 75 Years, accepts healthy volunteers

Inclusion Criteria:

1. 18 to 75 (inclusive) years of age on the date when ICF was signed;
2. Histologically or cytologically confirmed renal clear cell carcinoma;
3. Patients with locally advanced/metastatic renal carcinoma;
4. Patients with renal carcinoma who progressed during or after or intolerant to previous first-line VEGFR-TKI therapy for advanced/metastatic disease;
5. At least 1 measurable lesion according to RECIST 1.1;
6. ECOG PS of 0 or 1;
7. Adequate organ function.

Exclusion Criteria:

1. Had previously received therapy targeting immune modulatory receptors or related pathways (including but not limited to therapy targeting PD-1, CTLA-4, IDO, PD-L1, LAG-3, TIGIT, IL-2R and GITR, etc, but excluding related cytokine therapy such as IL2), excluding patients who had received immunotherapy such as anti-PD- (L) 1 antibody in adjuvant/neoadjuvant therapy setting and did not progress within 6 months after discontinuation;
2. Receiving approved systemic anti-tumor therapy within 2 weeks prior to the first dose;
3. Toxicities caused by prior anti-tumor therapy before the first dose that did not recover to Grade 0 or 1 per the NCI CTCAE v5.0 or to the level specified in the enrollment criteria (excluding alopecia and peripheral neurotoxicity ≤ CTCAE Grade 2);
4. Immunosuppression medication within 4 weeks prior to randomization;
5. Patients with active autoimmune or inflammatory diseases;
6. Known central nervous system (CNS) metastasis;
7. History of pneumonitis requiring corticosteroid therapy, or history of or current interstitial lung disease, or current active pulmonary infection, etc.;
8. Toxicities caused by prior anti-tumor therapy before the first dose that did not recover to Grade 0 or 1 per the National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) v5.0 or to the level specified in the enrollment criteria (excluding alopecia and peripheral neurotoxicities ≤CTCAE Grade 2 caused by platinum-based chemotherapy; thyroid dysfunction with stable disease control after symptomatic treatment);
9. Human Immunodeficiency Virus (HIV) Infection (HIV 1/2 Antibody positive);
10. Uncontrolled hypertension despite standard therapy;
11. Patient with evidence or history of haemorrhagic tendency within 2 months prior to the first dose, regardless of severity.

• Dingwei Ye, Principal investigator, Fudan University
• Zhi Song He, Principal investigator, Peking University First Hospital