NCT04195750进行中（未招募）3 期
An Open-label, Randomized Phase 3 Study of MK-6482 Versus Everolimus in Participants With Advanced Renal Cell Carcinoma That Has Progressed After Prior PD-1/L1 and VEGF-Targeted Therapies
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 755
- 试验地点
- 341
- 主要终点
- Progression-free Survival (PFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
研究概览
简要总结
The primary objective of this study is to compare belzutifan to everolimus with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) and to compare everolimus with respect to overall survival (OS). The hypothesis is that belzutifan is superior to everolimus with respect to PFS and OS.
详细描述
Per protocol, all participants enrolled in the Safety Run-In were not randomized and not included in the protocol-specified analyses for any of the outcome measures.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Has unresectable, locally advanced or metastatic clear cell renal cell carcinoma (RCC)
- •Has had disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with both Programmed cell death 1 ligand 1 (PD-1/L1) checkpoint inhibitor and a vascular endothelial growth factor - tyrosine kinase inhibitor (VEGF-TKI) in sequence or in combination
- •Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC
- •A male participant is eligible to participate if he is abstinent from heterosexual intercourse or agrees to use contraception during the intervention period and for at least 7 days after the last dose of study intervention
- •A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 30 days after the last dose of study intervention for those randomized to belzutifan and for at least 8 weeks after the last dose of study intervention for those randomized to everolimus
- •The participant (or legally acceptable representative if applicable) has provided documented informed consent for the study
- •Has adequate organ function
排除标准
- •Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. (Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ [e.g., breast carcinoma, cervical cancer in situ] that have undergone potentially curative therapy are not excluded)
- •Has known central nervous system (CNS) metastases and/or carcinomatous meningitis. (Participants with previously treated brain metastases may participate provided they are radiologically stable for at least 4 weeks (28 days) by repeat imaging)
- •Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study medication administration, or New York Heart Association Class III or IV congestive heart failure. (Medically controlled arrhythmia stable on medication is permitted)
- •Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg
- •Has moderate to severe hepatic impairment (Child-Pugh B or C)
- •Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
- •Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption)
- •Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan or everolimus) formulations
- •Has received prior treatment with belzutifan or another hypoxia inducible factor 2α (HIF-2α inhibitor)
- •Has received prior treatment with everolimus or any other specific or selective target of rapamycin complex 1 (TORC1)/ phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) inhibitor (e.g., temsirolimus) in the advanced disease setting
- •Has received any type of systemic anticancer antibody (including investigational antibody) within 4 weeks before randomization
- •Has received prior radiotherapy within 2 weeks prior to randomization
- •Has had major surgery within 3 weeks prior to randomization
- •Has received a live vaccine within 30 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed
- •Is currently receiving either strong (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study
- •Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study
- •Is currently participating in a study of an investigational agent or is currently using an investigational device
- •Has an active infection requiring systemic therapy
- •Has active bacillus tuberculosis (TB)
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
- •Has a known history of human immunodeficiency virus (HIV) infection. (Testing for HIV at screening is only required if mandated by local health authority
- •Has a known history of Hepatitis B virus (HBV) (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV) (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection
研究组 & 干预措施
Belzutifan
Experimental
Randomized participants received 120 mg of belzutifan orally once daily (QD), until disease progression or discontinuation.
干预措施: Belzutifan (Drug)
Safety Run-In
Experimental
Non-Randomized participants enrolled into the Safety Run-in received up to 120 mg of belzutifan QD.
干预措施: Belzutifan (Drug)
Everolimus
Active Comparator
Randomized participants received 10 mg of Everolimus orally QD, until disease progression or discontinuation.
干预措施: Everolimus (Drug)
结局指标
主要结局
Progression-free Survival (PFS) Per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
时间窗: Up to approximately 39 months
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by blinded independent central review is presented here.
Overall Survival (OS)
时间窗: Up to approximately 49 months
OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.
次要结局
- Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR(Up to approximately 31 months)
- Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR(Up to approximately 49 months)
- Number of Participants Who Experience One or More Adverse Events (AEs)(Up to approximately 78 months)
- Number of Participants Who Discontinue Study Treatment Due to an AE(Up to approximately 78 months)
- Time to True Deterioration (TTD) in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Combined Score(Up to approximately 39 months)
- TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score(Up to approximately 39 months)
- TTD in Disease Symptoms Using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) Items 1-9 Score(Up to approximately 39 months)
- Change From Baseline to Week 17 in the HRQoL Using the EORTC QLQ-C30 Items 29 and 30 Combined Score(Baseline (Day 1) and week 17)
- Change From Baseline to Week 17 in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score(Baseline (Day 1) and week 17)
- Change From Baseline to Week 17 in Disease Symptoms Using the FKSI-DRS Items 1-9 Score(Baseline (Day 1) and week 17)
- Change From Baseline to Week 17 in Visual Analogue Scale (VAS) Score on the European Quality of Life 5 Dimension, 5-level Questionnaire (EQ-5D-5L) Health Utility Score(Baseline (Day 1) and week 17)
研究者
研究点 (341)
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相关资讯
Belzutifan Demonstrates Superior Quality-Adjusted Survival Time Compared to Everolimus in Advanced Renal Cell Carcinoma- Belzutifan showed a clinically meaningful 2.66-month improvement in quality-adjusted time without symptoms or toxicity (Q-TWiST) compared to everolimus in advanced renal cell carcinoma patients.
- The phase 3 LITESPARK-005 trial demonstrated an 11.32% relative gain in Q-TWiST with belzutifan, despite numerically longer time with grade 3/4 toxicity.
- Belzutifan patients experienced significantly longer time without symptoms and progression (10.73 vs 6.07 months) driven by prolonged periods without disease progression.
- The analysis supports belzutifan's clinical benefit profile, with lead investigator Thomas Powles noting superior response rates, progression-free survival, and quality of life outcomes.last yearBelzutifan Approved in China for VHL-Associated Tumors- China's NMPA has approved belzutifan (Welireg) for adult patients with von Hippel-Lindau (VHL) disease requiring therapy for associated renal cell carcinoma, CNS hemangioblastomas, or pancreatic neuroendocrine tumors.
- The approval was based on the phase 2 LITESPARK-004 trial, which demonstrated an objective response rate of 49% in patients with VHL-associated RCC and notable responses in CNS hemangioblastomas and pNETs.
- Belzutifan, a HIF-2α inhibitor, offers a non-surgical treatment option for VHL patients in China, addressing a significant unmet medical need for systemic therapy.
- This marks the 17th global approval for belzutifan in treating VHL-associated tumors, previously approved by the FDA in August 2021 and December 2023 for specific RCC indications.last year