Study of Lenvatinib in Combination With Everolimus in Participants With Unresectable Advanced or Metastatic Renal Cell Carcinoma (RCC)

Study Overview
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Brief Summary
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Phase 1 study to investigate the tolerability and safety of lenvatinib in combination with Everolimus in participants with unresectable advanced or metastatic RCC.

Official Title
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Phase 1 Study of Lenvatinib in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic RCC

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Drug: Lenvatinib
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary agreement to provide written informed consent of this study. Willing and able to comply with all aspects of the protocol after being fully informed of the content. Males or females aged greater than or equal to 20 years at the time of informed consent. Histological or cytological confirmation of RCC. Participants must have confirmed diagnosis of unresectable advanced and/or metastatic RCC. Disease progression following vascular endothelial growth factor (VEGF) targeted therapy. Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 to 1. Adequately controlled blood pressure with or without the use of antihypertensive agents. Participants with adequate function of major organs. Adequate blood coagulation function, defined as international normalized ratio (INR) less than or equal to 1.5. Survival expectation of 3 months or longer after study enrollment. Participants with adequate washout period from the end of prior treatment to the start of study drug administration. Females of childbearing potential must not have had unprotected sexual intercourse within 28 days before participant registration and must agree to use a highly effective method of contraception throughout the entire study period and for 30 days after final administration of investigational drug. If currently abstinent, the participant must agree to use a double-barrier method as described above if she becomes sexually active during this study period or for 30 days after investigational drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before administration and must continue to use the same contraceptive during this study and for 30 days after investigational drug discontinuation. Male participants and their female partners must meet the criteria above. Exclusion Criteria: Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy 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 brain metastases must be stable for at least 4 weeks before starting study treatment. Prior exposure to lenvatinib. Participants who have not recovered from toxicities to less than or equal to Grade 1 as a result of prior anticancer therapy, except alopecia. Major surgery within 3 weeks prior to the first dose of lenvatinib. Participants with a urine protein greater than or equal to 1 gram per 24 hours (g/24 hours). Uncontrollable diabetes as defined by fasting glucose greater than 1.5* upper limit of normal (ULN). Fasting total cholesterol greater than 7.75 millimole per liter (mmol/L) (greater than 300 milligram per decilitre [mg/dL]). Fasting triglycerides greater than 2.5 * ULN. Any condition that might affect the absorption of lenvatinib and/or everolimus. Significant cardiovascular impairment. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR monitoring. Active hemoptysis. Active infections that require systemic treatment. Human immunodeficiency virus (HIV) positive. Hepatitis B virus (HBV). A history of interstitial pneumonia with clinical manifestation or as confirmed by means of diagnostic imaging. Medical need for the continued use of potent or moderate inhibitors of cytochrome P450 3A (CYP3A) or P-gp, or potent or moderate inducer of CYP3A. Known intolerance to lenvatinib (or any of the excipients) or known hypersensitivity to everolimus (or any of the excipients) or rapmycins (sirolimus, temsirolimus and so on). Alcohol or drug dependency or abuse, inability to comply with every aspects of the study protocol, or any physical or mental conditions that in the opinion of the investigators would preclude the participant's participation in the study. Females who are pregnant or breastfeeding (not eligible even she discontinues breastfeeding). Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenvatinib plus Everolimus<br> | Drug: Lenvatinib<br> <br> Drug: Everolimus<br> <br> * Other names: Lenvatinib plus Everolimus orally once a day;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT) | DLT was defined as toxicity related to the combination therapy and was graded according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). | From first dose of study drug up to Cycle 1 Day 28 (Cycle length=28 days) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Baseline up to 30 days after the last dose of study drug (up to approximately 21.5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for Levatinib and Everolimus |  | Cycle 1 Day 1 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | 
| Css,Max: Maximum Observed Plasma Concentration at Steady State for Levatinib and Everolimus |  | Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Levatinib and Everolimus |  | Cycle 1 Day 1 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | 
| Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State for Levatinib and Everolimus |  | Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | 
| AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Levatinib and Everolimus |  | Cycle 1 Day 1 and Cycle 1 Day 15 predose and at 1, 2, 4 ,8, and 24 hours postdose (Cycle length=28 days) | 
| Number of Participants With Best Overall Response (BOR) | BOR included complete response (CR), partial response (PR), stable disease (SD), and PD (progressive disease). BOR was assessed using Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 | From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months) | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants who achieved BOR of CR or PR. ORR was assessed using RECIST 1.1. | From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months) | 
| Disease Control Rate (DCR) | DCR was defined as the percentage of participants who achieved BOR of CR, PR, or SD. DCR was assessed based on RECIST 1.1. | From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 23 months) | 
| Number of Participants With the Minimum Percent Change From Baseline in the Sum of Diameters of Target Lesions |  | Baseline up to first tumor assessment at which diameter of target lesions were available (up to approximately 23 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic renal cell carcinoma, lenvatinib, Everolimus, Carcinoma, Unresectable advanced renal cell carcinoma