Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma

Study Overview
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Brief Summary
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The primary purpose of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progression-free survival (PFS) (by independent imaging review [IIR] using Response Evaluation Criteria in Solid Tumors [RECIST 1.1]) as first-line treatment in participants with advanced renal cell carcinoma (RCC).

Official Title
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A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination With Everolimus or Pembrolizumab Versus Sunitinib Alone in First-Line Treatment of Subjects With Advanced Renal Cell Carcinoma (CLEAR)

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Lenvatinib
* Drug: Everolimus
* Drug: Pembrolizumab
* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmation of RCC with a clear-cell component (original tissue diagnosis of RCC is acceptable). Documented evidence of advanced RCC. At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria: Lymph node (LN) lesion that measures at least 1 dimension as greater than or equal to (>=) 1.5 cm in the short axis Lymph node (LN) lesion that measures at least 1 dimension as greater than or equal to (>=) 1.5 centimeter (cm) in the short axis Non-nodal lesion that measures greater than or equal to (>=) 1.0 cm in the longest diameter The lesion is suitable for repeat measurement using computerized tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion. 3.Karnofsky Performance Status (KPS) of >=70 4.Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal (<=) 150/90 millimeter of mercury (mmHg) at Screening and no change in antihypertensive medications within 1 week prior to Cycle 1/Day 1 (C1/D1) 5.Adequate renal function defined as creatinine <=1.5*upper limit of normal (ULN); or for participants with creatinine greater than (>) 1.5*ULN, the calculated creatinine clearance >=30 milliliters per minute (mL/min) (per the Cockcroft-Gault formula) is acceptable. 6.Adequate bone marrow function defined by: Absolute neutrophil count (ANC) >=1500/cubic millimeter (mm^3) Platelets >=100,000/mm^3 Hemoglobin >=9 grams per deciliter (g/dL) NOTE: Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within the previous 2 weeks. 7.Adequate blood coagulation function defined by International Normalized ratio (INR) <=1.5 unless participant is receiving anticoagulant therapy, as long as INR is within therapeutic range of intended use of anticoagulants. 8.Adequate liver function defined by: Total bilirubin <=1.5*ULN except for unconjugated hyperbilirubinemia of Gilbert's syndrome. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3*ULN (in the case of liver metastases <=5*ULN), unless there are bone metastases. Participants with ALP values >3*ULN and known to have bone metastases can be included. 9.Provide written informed consent. 10.Willing and able to comply with all aspects of the protocol. Exclusion Criteria: Participants who have received any systemic anticancer therapy for RCC, including anti-vascular endothelial growth factor (VEGF) therapy, or any systemic investigational anticancer agent. Prior adjuvant treatment with an investigational anticancer agent is not allowed unless the investigator can provide evidence of participant's randomization to placebo arm. Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy (example, whole brain radiation therapy (WBRT), surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (example, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study treatment Active malignancy (except for RCC, definitively treated basal or squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix or bladder) within the past 24 months. Participants with history of localized & low risk prostate cancer are allowed in the study if they were treated with curative intent and there is no prostate specific antigen (PSA) recurrence within the past 5 years Prior radiation therapy within 21 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start Participants who are using other investigational agents or who had received investigational drugs <=4 weeks prior to study treatment start. Received a live vaccine within 30 days of planned start of study treatment (Cycle 1/Day 1). Examples of live vaccines include, but are not limited to, 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 (example, FluMist®) are live attenuated vaccines and are not allowed. Participants with proteinuria >1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 g/24 h will be ineligible Fasting total cholesterol >300 milligram per deciliter (mg/dL) (or ˃7.75 millimole per liter (mmol/L)) and/or fasting triglycerides level ˃2.5 x upper limit of normal (ULN). Note: these participants can be included after initiation or adjustment of lipid-lowering medication Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. Note: these participants can be included after initiation or adjustment of glucose-lowering medication Prolongation of corrected QT (QTc) interval to >480 milliseconds (ms) Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib, everolimus, and/or sunitinib. Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug Significant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association Class II, unstable angina, myocardial infarction, cerebrovascular accident, or cardiac arrhythmia associated with hemodynamic instability. The following is also excluded: left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multiple-gated acquisition MUGA scan or echocardiogram Active infection (any infection requiring systemic treatment) Participants known to be positive for Human Immunodeficiency Virus (HIV). Known active Hepatitis B (example, Hepatitis B surface antigen (HBsAg) reactive) or Hepatitis C (example, hepatitis C virus ribonucleic acid (HCV RNA) [qualitative] is detected) Known history of, or any evidence of, interstitial lung disease Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis Participants with a diagnosis of immunodeficiency or who are receiving chronic systemic steroid therapy (doses exceeding 10 mg/day of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Physiologic doses of corticosteroids (up to 10 mg/day of prednisone or equivalent) may be used during the study Active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years (that is, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (example, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. Females of childbearing potential who: Do not agree to use a highly effective method of contraception for the entire study period and for 120 days after study discontinuation, that is: total abstinence (if it is their preferred and usual lifestyle) an intrauterine device (IUD) or hormone-releasing system (IUS) a contraceptive implant an oral contraceptive (with additional barrier method) OR Do not have a vasectomized partner with confirmed azoospermia. For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, that is, double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide. Males who have not had a successful vasectomy (confirmed azoospermia) and do not agree to use condom + spermicide OR have a female partner who does not meet the criteria above (that is, is of childbearing potential and not practicing highly effective contraception throughout the study period), starting with the first dose of study therapy through 120 days after the last dose of study therapy, unless sexually abstinent. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant. Known intolerance to any of the study drugs (or any of the excipients) Participant has had an allogenic tissue/solid organ transplant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Lenvatinib 18 mg plus Everolimus 5 mg<br>Lenvatinib 18 milligrams (mg) administered orally, once daily, plus everolimus 5 mg administered orally, once daily in each 21-day cycle. | Drug: Lenvatinib<br> <br> Drug: Everolimus<br> <br> |
| Experimental: Lenvatinib 20 mg plus Pembrolizumab 200 mg<br>Lenvatinib 20 mg administered orally, once daily, in each 21-day cycle plus pembrolizumab 200 mg administered intravenously (IV), every 3 weeks on Day 1 of each 21-day cycle. | Drug: Lenvatinib<br> <br> Drug: Pembrolizumab<br> <br> |
| Active Comparator: Sunitinib 50 mg<br>Sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment in each 21-day cycle. | Drug: Sunitinib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) by Independent Imaging Review (IIR) | PFS assessed by IIR was defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or death (whichever occurred first) using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). PD was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier method. | From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to data cutoff date 28 Aug 2020 (up to approximately 46 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by IIR using RECIST 1.1. CR is defined as disappearance of all (targeted and non-target [NT]) lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of death from any cause. Participants who were lost to follow-up and those who were alive at the data cutoff date were censored, either at the last date the participant was last known alive or at the data cutoff date, whichever occurred first. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| Number of Participants With At Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 30 days after the last dose of study drug.An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A SAE was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| Number of Participants Who Discontinued Treatment Due to Toxicity | Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| Time to Treatment Failure Due to Toxicity | Time to treatment failure due to toxicity is defined as time from the date of randomization to the date that a participant discontinued study treatment due to TEAEs. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores | The FKSI-DRS consisted of 9 items that experts and participants had indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts had indicated are primarily disease-related, as opposed to treatment-related. Symptoms assessed on the FKSI-DRS included lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or hematuria. Each item was scored on a 5-point Likert-type scale (0 = not at all; 4 = very much) where total score ranged from 0 (worst) to 36 (best), where higher scores correspond to better outcomes. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| HRQoL Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Score | EORTC QLQ-C30 is a questionnaire including 30 questions that rate the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. For the overall HRQoL and functioning scales, a higher score is correlated with better HRQoL, whereas a higher score represents worse HRQoL for symptom scales. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Score | EQ-5D-3L is a health profile questionnaire consisting of the EQ-5D descriptive system and the EuroQol visual analog scale (EQ-VAS). For the EQ-5D, participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) at 1 of 3 levels (1=no problems; 2=some problems; 3=extreme problems). The EQ-5D Health Utilities Index (HUI) is derived from the five dimensions of the EQ-5D, using country-specific preference weights (tariffs) to summarize how good or bad each health state is on a scale from 1 (full health) to <0 (worse health/dead). The EQ-VAS measures self-rated global health status using a vertically oriented VAS, where 100 represents the best imaginable health state and 0 represents the worst imaginable health state. Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| PFS on Next-line of Therapy (PFS2) | PFS2 is defined as the time from randomization to disease progression as assessed by investigator on next-line treatment or death from any cause (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| PFS by Investigator Assessment | PFS by investigator assessment is defined as the time from the date of randomization to the date of first documentation of disease progression based on the investigator assessment per RECIST 1.1 or death (whichever occurred first). Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Up to approximately 69 months | 
| Model-predicted Clearance for Lenvatinib and Everolimus | Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length=21 days) | 
| Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib and Everolimus | Data for this outcome measure will be reported after study completion (anticipated study completion date is July 2022). | Cycles 1 and 2 Day 1; 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycles 3, 4, 5 and 6 Day 1: predose (Cycle length = 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment-naive RCC, Renal Cell Carcinoma (RCC), Lenvatinib, First-line RCC, Everolimus, Pembrolizumab, Sunitinib, Phase 3 RCC, Phase 3 first-line RCC, Phase 3 treatment-naive RCC