Trial to Assess Safety and Efficacy of Lenvatinib (18 mg vs. 14 mg) in Combination With Everolimus in Participants With Renal Cell Carcinoma

Study Overview
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Brief Summary
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Study E7080-G000-218 is a Randomized, open-label (formerly Double-blind), Phase 2 Trial conducted to assess whether a starting dose of lenvatinib 14 milligrams (mg) in combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective response rate [ORR] at 24 weeks [ORR24W]) with an improved safety profile compared to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment-emergent intolerable Grade 2, or any greater than or equal to (>=) Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Official Title
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A Randomized, Open-Label (Formerly Double-Blind), Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at Two Different Starting Doses (18 mg vs. 14 mg QD) in Combination With Everolimus (5 mg QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: lenvatinib
* Drug: everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmation of predominant clear cell renal cell carcinoma (RCC) (original tissue diagnosis of RCC is acceptable) Documented evidence of advanced RCC One prior disease progression episode on or after vascular endothelial growth factor (VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) administered for the treatment of RCC. Prior programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) treatment in addition to 1 prior VEGF-targeted treatment is allowed. At least 1 measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) meeting the following criteria: Lymph node (LN) lesion that measures at least 1 dimension as >=1.5 centimeter (cm) in the short axis; Non-nodal lesion that measures >=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. Male or female participants age >=18 years (or any age >=18 years if that age is considered to be an adult per the local jurisdiction) at the time of informed consent Karnofsky Performance Status (KPS) of >=70 Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to (<=) 150/90 millimeters of mercury (mmHg) at Screening and no change in antihypertensive medications within 1 week before Cycle 1/Day 1 Adequate renal function defined as calculated creatinine clearance >=30 milliliters per minute (mL/min) per the Cockcroft and Gault formula Adequate bone marrow function defined by: Absolute neutrophil count (ANC) >=1500/millimeters cubed (mm^3) (>=1.5*10^9/Liters [L]); Platelets >=100,000/mm^3 (>=100*10^9/L); Hemoglobin >=9 grams per deciliter (g/dL) Adequate blood coagulation function defined by International Normalized Ratio (INR) <=1.5 (except for participants on warfarin therapy where INR must be <=3.0 prior to randomization) Adequate liver function defined by: Total bilirubin <=1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome; Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3* the ULN (in the case of liver metastases <=5* the ULN). Participants with bone metastases with ALP values greater than 3 times can be included. Participant must voluntarily agree to provide written informed consent Participant must be willing and able to comply with all aspects of the protocol Exclusion Criteria: More than 1 prior VEGF-targeted treatment for advanced RCC Participants with Central Nervous System (CNS) metastases are not eligible, unless they have completed local therapy for at least 4 weeks and have discontinued the use of corticosteroids for this indication or are on a tapering regimen of corticosteroids (defined as <=10 mg prednisolone equivalent) before starting treatment in this study. Any signs (example, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. Active malignancy (except for RCC or definitively treated basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 months Any anti-cancer treatment (except for radiation therapy) within 21 days, or any investigational agent within 30 days prior to the first dose of study drug; participants should have recovered from any toxicity related to previous anti-cancer treatment to Common Toxicity Criteria (CTC) grade 0 or 1. Prior radiation therapy within 21 days prior to the 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 Known intolerance to study drug (or any of the excipients) and/or known hypersensitivity to rapamycins (example, sirolimus, everolimus, temsirolimus) or any of the excipients Participants with proteinuria greater than (>) 1+ on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 g/24 hour will be ineligible. Fasting total cholesterol ˃300 mg/dL (or ˃7.75 millimoles [mmol]/L) and/or fasting triglycerides level ˃2.5* the 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 QT corrected (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 or everolimus Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (example, carotid artery) 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 6 months prior to the first dose of study drug; history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke, or cardiac arrhythmia associated with significant cardiovascular impairment or left ventricular ejection fraction (LVEF) below the institutional normal range as determined by screening multigated acquisition (MUGA) scan or echocardiogram. Active infection (any infection requiring systemic treatment) Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 International Units per Liter [IU/L] or equivalent units of β-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 (Note: all females will be considered to be of childbearing potential unless they are postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [that is, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing].): do not agree to use a highly effective method of contraception for the entire study period and for up to 8 weeks after study drug 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) (Note: Participants must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study.) OR do not have a vasectomized partner with confirmed azoospermia For sites outside of the European Union, 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.

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 14 mg plus everolimus 5 mg<br>Participants will receive oral lenvatinib 14 mg once daily (QD) plus oral everolimus 5 mg QD as the starting dose for Cycle 1. If there are no intolerable Grade 2 or any >= Grade 3 treatment-emergent adverse events (TEAEs) that require dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), the lenvatinib dose will be escalated to 18 mg QD (plus everolimus 5 mg) beginning in Cycle 2 or later (cycle length equal to [=] 28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles. | Drug: lenvatinib<br>* lenvatinib capsules.<br>Drug: everolimus<br>* everolimus tablets.<br>|
| Experimental: Lenvatinib 18 mg plus everolimus 5 mg<br>Participants will receive oral lenvatinib 18 mg QD plus oral everolimus 5 mg QD as the starting dose in Cycle 1 or later (cycle length =28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles. | Drug: lenvatinib<br>* lenvatinib capsules.<br>Drug: everolimus<br>* everolimus tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate at Week 24 (ORR24W) | ORR24W was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at the Week 24 (after randomization) time point, during treatment or within 28 days after the last dose date but on or prior to the start of new anticancer therapy based on investigator assessment according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10 millimeters (mm). PR: defined as at least a 30 percent (%) 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. | At Week 24 | 
| Percentage of Participants With Intolerable Grade 2 or Any Grade >=Grade 3 TEAEs Within 24 Weeks | TEAE was defined as an adverse event (AE) with an onset that had occurred after receiving study drug. A severity grade was defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. As per NCI-CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE. | Up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from the date of randomization to the date of the first documentation of PD by investigator assessment or date of death, whichever occurred first according to RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter (SOD) of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Median PFS was analyzed using the Kaplan-Meier product-limit estimates for each treatment group and presented with 2-sided 95% confidence interval (CI). | From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to date of data cutoff for the primary analysis (up to 29 months) | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants with a BOR of CR or PR at the at the end of treatment based on investigator assessment according to RECIST v1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. 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. | From date of randomization up to first documentation of PD or date of death, whichever occurred first or up to the date of data cut off for the primary analysis (up to 29 months) | 
| Number of Participants With TEAEs and Serious TEAEs | TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 28 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 serious adverse event (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. | From date of first dose of study drug up to 28 days after last dose of study drug, or date of data cut off for the primary analysis (up to 29 months) | 
| Percentage of Participants Who Discontinued Treatment Due to Toxicity | Percentage of participants who discontinued treatment due to toxicity, defined as the percentage of participants who discontinued study treatment due to TEAEs. Toxicity (except hypertension and non-infectious pneumonitis) was assessed according to NCI-CTCAE v4.03. | From date of first dose of study drug up to 28 days after last dose of study drug, or date of data cut off for the primary analysis (up to 29 months) | 
| Time to Treatment Failure Due to Toxicity | Time to treatment failure due to toxicity was defined as the time from the date of randomization to the date that a participant discontinued study treatment due to TEAEs. Toxicity (except hypertension and non-infectious pneumonitis) was assessed according to CTCAE v4.03. | From the date of randomization to the date of discontinuation of study treatment due to TEAEs, or date of data cut off for the primary analysis (up to 29 months) | 
| Overall Survival (OS) | OS was defined as the time from the date of randomization until the date of death from any cause. In the absence of confirmation of death, participants will be censored either at the date that the participant was last known to be alive or the date of data cutoff for the primary analysis, whichever comes earlier. Median OS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. | From the date of randomization until the date of death from any cause, or up to date of data cut off for the primary analysis (up to 29 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. | At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months) | 
| HRQoL Assessed by European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 Scores | The EORT QLQ-C30 consisted of 30 questions comprising 9 multiple-item scales and 6 single items. Multiple-item scales of QLQ-C30 consisted of 5 functional scales (physical, role, emotional, cognitive, and social) and 3 symptom scales (fatigue, nausea and vomiting, pain) and a global health status/QOL score. Six single-item scales of QLQ-C30 involved dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties. First 28 questions used a 4-point scale (1 = Not at all to 4 = Very much); and last 2 questions used a 7-point scale (1 = Very poor to 7 = Excellent). Scores for all scales range from 0 to 100. For the overall HRQoL and functioning scales, a higher score was correlated with better HRQoL, whereas a higher score for symptom scales represented worse HRQoL. | At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months) | 
| HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS) | The EQ-5D-3L is a health profile questionnaire assessing quality of life along 5 dimensions. Participants rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 5-15 with 5 corresponding to no problems and 15 corresponding to severe problems in the 5 dimensions. The EQ-5D index was calculated by applying preference-based weights (tariffs) to the scores of the five health state dimensions. Index values can range from -1 to 1, with 0 representing a health state equivalent to death and 1 representing perfect health. EQ-5D-3L also included an EQ visual analogue scale (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best). | At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months) | 
| Progression-free Survival After Next Line of Therapy (PFS2) | PFS2, defined as the time from randomization to the date of PD after next line of therapy or death from any cause, whichever occurred first based on investigator assessment according to RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Median PFS2 was analyzed using the Kaplan-Meier product-limit estimates for each treatment group and presented with 2-sided 95% CI. | From the time of randomization to the date of PD after next line of therapy or death from any cause or the date of data cutoff for the primary analysis, whichever occurs first (up to 29 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Cell Carcinoma, lenvatinib, everolimus, E7080, VEGF-targeted treatment