Efficacy and Safety of Fruquintinib in Combination With Sintilimab in Advanced Renal Cell Carcinoma

Study Overview
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Brief Summary
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The study consists of two parts, the first part is a randomized, open-label, active-controlled study to evaluate the efficacy and safety of fruquintinib in combination with sintilimab versus axitinib or everolimus montherapy as second-line treatment for locally advanced or metastatic renal cell carcinoma. The second part is a fruquintinib montherapy factorial cohort study to evaluate the efficacy and safety of fruquintinib monotherapy as for second-line treatment of locally advanced or metastatic renal cell carcinoma.

Detailed Description
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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.

Official Title
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A Phase II/III Clinical Study to Evaluate the Efficacy and Safety of Fruquintinib in Combination With Sintilimab Versus Axitinib or Everolimus as Second-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma

Conditions
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Advanced Renal Cell Carcinoma

Intervention / Treatment
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* Drug: fruquintinib+sintilimab
* Drug: axitinib / everolimus
* Drug: fruquintinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 75 (inclusive) years of age on the date when ICF was signed; Histologically or cytologically confirmed renal clear cell carcinoma; Patients with locally advanced/metastatic renal carcinoma; Patients with renal carcinoma who progressed during or after or intolerant to previous first-line VEGFR-TKI therapy for advanced/metastatic disease; At least 1 measurable lesion according to RECIST 1.1; ECOG PS of 0 or 1; Adequate organ function. Exclusion Criteria: Had previously received therapy targeting immune modulatory receptors or related pathways; Receiving approved systemic anti-tumor therapy within 2 weeks prior to the first dose; 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); Immunosuppression medication within 4 weeks prior to randomization; Patients with active autoimmune or inflammatory diseases; Known central nervous system (CNS) metastasis; History of pneumonitis requiring corticosteroid therapy, or history of or current interstitial lung disease, or current active pulmonary infection, etc.; Known clinically significant history of hepatopathy, including active hepatitis virus infection, or other active hepatitis, clinically significant moderate to severe liver cirrhosis; Human Immunodeficiency Virus (HIV) Infection (HIV 1/2 Antibody positive); Uncontrolled hypertension despite standard therapy; Patient with evidence or history of haemorrhagic tendency within 2 months prior to the first dose, regardless of severity.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational arm<br>fruquintinib, 5 mg, QD, PO, 2 weeks on/1 week off, 3 weeks/cycle; sintilimab, 200 mg, IV infusion, Q3W, 3 weeks/cycle. | Drug: fruquintinib+sintilimab<br>* fruquintinib, 5 mg, QD, PO, 2 weeks on/1 week off, 3 weeks/cycle; sintilimab, 200 mg, IV infusion, Q3W, 3 weeks/cycle.<br>* Other names: HMPL-013 + IBI308;|
| Active Comparator: Control arm (comparator)<br>axitinib, 5 mg, twice daily (BID), PO, 3 weeks/cycle, dose escalation will be at the investigator 's discretion ;Everolimus, 10 mg, QD, PO, 3 weeks/cycle. | Drug: axitinib / everolimus<br>* 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.<br>|
| Other: Fruquintinib monotherapy factorial study<br>fruquintinib, 5 mg, QD, PO, 3 weeks on/ 1 week off, 4 weeks/cycle. | Drug: fruquintinib<br>* fruquintinib, 5 mg, QD, PO, 3 weeks on/ 1 week off, 4 weeks/cycle.<br>* Other names: HMPL-013;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) in Part I | PFS per RECIST 1.1 by BIRC | 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. | 
| Objective response rate (ORR) in Part II | ORR per RECIST 1.1 by investigator | Time from the date of first treatment administration until disease progression or the introduction of a new treatment, assessed up to 20 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | PFS per RECIST 1.1 | 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. | 
| Safety in Part I | Severity and Incidence of Adverse event (AEs) and findings in Laboratory test, vital signs, 12-lead Electrocardiogram (ECG), etc. in Part I | Through study completion, assessed up to 20 months. | 
| Quality of life in Part I | Quality of life Questionnare analysis in Part I | Through study completion, assessed up to 20 months. | 
| Safety in Part II | Severity and incidence of AEs and findings in such as Laboratory test, vital signs, 12-lead ECG, etc. in Part II. | Through study completion, assessed up to 20 months. | 
| Disease control rate (DCR) | PFS per RECIST 1.1 | 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 | ORR per RECIST 1.1 | 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. | 
| Duration of response (DoR) | DoR per RECIST 1.1 | 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. | 
| Time to Response (TTR) | TTR per RECIST 1.1 | 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. | 
| OS | OS | Time from date of randomization until the date of death from any cause, assessed up to 20 months. |