Clinical Trials /

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

NCT03173560

Description:

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 ≥ Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial to Assess Safety and Efficacy of Lenvatinib in Combination With Everolimus in Participants With Renal Cell Carcinoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: E7080-G000-218
  • SECONDARY ID: 2016-002778-11
  • NCT ID: NCT03173560

Conditions

  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
lenvatinibLenvatinib 18 mg plus everolimus 5 mg
everolimusLenvatinib 18 mg plus everolimus 5 mg

Purpose

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 ≥ Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Trial Arms

NameTypeDescriptionInterventions
Lenvatinib 18 mg plus everolimus 5 mgExperimentalParticipants will receive oral lenvatinib 18 milligrams (mg) once daily (QD) plus oral everolimus 5 mg QD as the starting dose in Cycle 1.
  • lenvatinib
  • everolimus
Lenvatinib 14 mg plus everolimus 5 mgExperimentalParticipants 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.
  • lenvatinib
  • everolimus

Eligibility 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 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 [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 up to 8 weeks 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description: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.
Measure:ORR as assessed by the investigator according to RECIST 1.1 at the end of treatment
Time Frame:up to approximately 4 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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).
Measure:Percentage of participants who discontinue treatment due to toxicity
Time Frame:up to approximately 4 years
Safety Issue:
Description:The percentage of participants who discontinue treatment due to toxicity is defined as the percentage of participants who discontinue study treatment due to TEAEs.
Measure: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)
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Individual lenvatinib and everolimus AUCs will be derived from the clearance and dose history data.
Measure: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
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:from the date of randomization until the date of death from any cause (up to approximately 4 years)
Safety Issue:
Description: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.
Measure: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, and at the Off-Treatment Visit (up to a maximum of 4 years)
Safety Issue:
Description: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).
Measure: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, and at the Off-Treatment Visit (up to a maximum of 4 years)
Safety Issue:
Description: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.
Measure: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, and at the Off-Treatment Visit (up to a maximum of 4 years)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Eisai Inc.

Trial Keywords

  • Renal Cell Carcinoma
  • lenvatinib
  • everolimus
  • E7080
  • VEGF-targeted treatment

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