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Trial to Assess Safety and Efficacy of Lenvatinib in Combination With Everolimus in Participants With Renal Cell Carcinoma

This study is currently recruiting participants.
Verified December 2017 by Eisai Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT03173560
First Posted: June 2, 2017
Last Update Posted: December 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Eisai Inc.
  Purpose
Study E7080-G000-218 is a Randomized, 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 ≥ Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Condition Intervention Phase
Renal Cell Carcinoma Drug: lenvatinib Drug: everolimus Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, 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

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Objective response rate (ORR) at Week 24 (ORR24W) as assessed by the investigator according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 [ Time Frame: Week 24 ]
    ORR24W is defined as the proportion of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) at the Week 24 (after randomization) time point or earlier. To be considered a BOR, all responses must be confirmed no less than 4 weeks after the initial assessment of response.

  • Percentage of participants with intolerable Grade 2 or any ≥ Grade 3 treatment-emergent adverse events (TEAEs) within 24 weeks after randomization (as of the Week-24 time point) [ Time Frame: Week 24 ]
    Adverse events (AEs) will be graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE is a list of AE terms commonly encountered in oncology. Each AE term is defined and accompanied by a grading scale that indicates the severity of the AE. Intolerable toxicities will be judged as such by the participant and/or physician to be intolerable.


Secondary Outcome Measures:
  • Progression-free survival (PFS) [ Time Frame: from the date of randomization to the date of the first documentation of disease progression or date of death, whichever occurs first (up to approximately 4 years) ]
    PFS is defined as the time from the date of randomization to the date of the first documentation of disease progression or date of death, whichever occurs first. For target lesions, progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). For non-target lesions, progressive disease is defined as the unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.

  • ORR as assessed by the investigator according to RECIST 1.1 at the end of treatment [ Time Frame: up to approximately 4 years ]
    ORR is defined as the proportion of participants with a best overall response (BOR) of CR or PR at the end of treatment. To be considered a BOR, all responses must be confirmed no less than 4 weeks after the initial assessment of response.

  • Percentage of participants with any treatment-emergent adverse event (TEAE) and percentage of participants with any serious TEAE [ Time Frame: up to approximately 4 years ]
    An AE is any untoward medical occurrence in a patient or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product. A serious TEAE is any untoward medical occurrence that at any dose: results in death; is life threatening (ie, the participant was at immediate risk of death from the AE as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).

  • Percentage of participants who discontinue treatment due to toxicity [ Time Frame: up to approximately 4 years ]
    The percentage of participants who discontinue treatment due to toxicity is defined as the percentage of participants who discontinue study treatment due to TEAEs.

  • Time to treatment failure due to toxicity [ Time Frame: from the date of randomization to the date of discontinuation of study treatment due to a TEAE (up to approximately 4 years) ]
    Time to treatment failure is defined as the time from the date of randomization to the date that a participant discontinues study treatment due to TEAEs.

  • Apparent clearance [ Time Frame: Cycle 1, Day 1 (C1D1) (each cycle is 28 days): 0.5 to 4 hours postdose, 6 to 10 hours postdose; C1D15: predose on Day 15, 0.5 to 4 hours postdose, 6 to 10 hours postdose; C2D1: predose on Day 1, 2 to 12 hours postdose ]
    The empirical Bayesian estimate of lenvatinib and everolimus apparent clearance for each participant will be obtained from the final pharmacokinetic (PK) model and the observed plasma concentration data.

  • Area under the plasma drug concentration-time curve (AUC) [ Time Frame: C1D1 (each cycle is 28 days): 0.5 to 4 hours postdose, 6 to 10 hours postdose; C1D15: predose on Day 15, 0.5 to 4 hours postdose, 6 to 10 hours postdose; C2D1: predose on Day 1, 2 to 12 hours postdose ]
    Individual lenvatinib and everolimus AUCs will be derived from the clearance and dose history data.

  • Population PK-derived AUC [ Time Frame: C1D1 (each cycle is 28 days): 0.5 to 4 hours postdose, 6 to 10 hours postdose; C1D15: predose on Day 15, 0.5 to 4 hours postdose, 6 to 10 hours postdose; C2D1: predose on Day 1, 2 to 12 hours postdose ]
    Lenvatinib and everolimus exposure parameters derived from the population PK analysis will be related to biomarker, safety, and efficacy data using a model-based approach.

  • Overall survival (OS) [ Time Frame: from the date of randomization until the date of death from any cause (up to approximately 4 years) ]
    OS will be measured 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, whichever comes earlier.

  • Health-Related Quality of Life (HRQoL) assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) scores [ Time Frame: Baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle, at time of early withdrawal, and at the Off-Treatment Visit (up to a maximum of 4 years) ]
    The FKSI-DRS consists of 9 items that experts and participants have indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts have indicated are primarily disease related, as opposed to treatment related. Symptoms assessed on the FKSI-DRS include pain, fatigue, shortness of breath, fevers, weight loss, coughing, and blood in urine. The total score can range from 0 (worst) to 36 (best).

  • HRQoL assessed by European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scores [ Time Frame: Baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle, at time of early withdrawal, and at the Off-Treatment Visit (up to a maximum of 4 years) ]
    The QLQ-C30 measure comprises 9 multiple-item scales and 6 single items. Multiple-item scales of QLQ-C30 consist of 6 functional scales (physical, role, emotional, cognitive, social and global QoL) and 3 symptom scales (fatigue, nausea and vomiting, pain). Six single-item scales of QLQ-C30 involve dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact. All of the derived scales range in scores from 0 to 100. For the overall Health Related Quality of Life (HRQoL) and functioning scales, a higher score is correlated with better HRQoL, whereas a higher score represents worse HRQoL for symptom scales.

  • HRQoL assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) questionnaire scores [ Time Frame: Baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle, at time of early withdrawal, and at the Off-Treatment Visit (up to a maximum of 4 years) ]

    The EQ-5D-3L generic QoL questionnaire is comprised of 5 dimensions: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Each dimension has 3 levels:

    (1) no problem, (2) some problem, or (3) extreme problem. Thus, the final scoring consists of 243 possible combinations or health states. The utility value for each state is assigned on the basis of a set of preference weights (tariffs) elicited from the general population.


  • PFS after next line of treatment (PFS2) [ Time Frame: the time from randomization to the date of disease progression after next line of therapy or death from any cause, whichever occurs first (up to approximately 4 years) ]
    PFS is defined as the time from the date of randomization to the date of the first documentation of disease progression or date of death, whichever occurs first. Progressive disease is defined as the unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.


Estimated Enrollment: 20
Actual Study Start Date: September 7, 2017
Estimated Study Completion Date: June 15, 2021
Estimated Primary Completion Date: January 15, 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lenvatinib 18 mg plus everolimus 5 mg
Participants will receive oral lenvatinib 18 milligrams (mg) once daily (QD) plus oral everolimus 5 mg QD as the starting dose in Cycle 1.
Drug: lenvatinib
lenvatinib capsules
Drug: everolimus
everolimus tablets
Experimental: Lenvatinib 14 mg plus everolimus 5 mg
Participants will receive oral lenvatinib 14 mg 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 (ie, the first 4 weeks of treatment), the lenvatinib dose will be escalated to 18 mg QD (plus everolimus 5 mg) beginning in Cycle 2.
Drug: lenvatinib
lenvatinib capsules
Drug: everolimus
everolimus tablets

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 ≤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 milligrams [mg] prednisolone equivalent) before starting treatment in this study. Any signs (eg, 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 (eg, sirolimus, everolimus, temsirolimus) or any of the excipients
  • Participants with proteinuria >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 (eg, 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
  • 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 [ie, 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 28 days after study drug discontinuation, ie:

      • 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, ie double barrier methods of contraception, such as condom plus diaphragm or cervical/vault cap with spermicide.

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03173560


Contacts
Contact: Eisai Medical Information 1-888-274-2378 esi_medinfo@eisai.com

  Show 32 Study Locations
Sponsors and Collaborators
Eisai Inc.
Investigators
Study Director: Daniel E Stepan, MD Eisai Global Study Director
  More Information

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT03173560     History of Changes
Other Study ID Numbers: E7080-G000-218
2016-002778-11 ( EudraCT Number )
First Submitted: May 22, 2017
First Posted: June 2, 2017
Last Update Posted: December 12, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc.:
Renal Cell Carcinoma
lenvatinib
everolimus
E7080
VEGF-targeted treatment

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Lenvatinib
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action