Clinical Trials List
Protocol NumberE7080-G000-218
NCT Number(ClinicalTrials.gov Identfier)NCT03173560
Completed
2017-05-01 - 2021-09-01
Phase II
Terminated4
ICD-10C64
Malignant neoplasm of kidney, except renal pelvis
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
-
Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
-
Sponsor
Eisai Inc.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/02/01
Investigators and Locations
Co-Principal Investigator
- Yen-Hwa Chang Division of Urology
- 沈書慧 Division of Radiology
- Yi-Hsiu Huang Division of Urology
- Tzu-Ping Lin Division of Urology
- Tzu-chun Wei Division of Urology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chuan-Shu Chen Division of Urology
- 盧嘉文 Division of Urology
- 裘坤元 Division of Urology
- 王樹吉 Division of Urology
- Jian-Ri Li Division of Urology
- Shian-Shiang Wang Division of Urology
- 熊小澐 Division of Radiology
- Chia-Yen Lin Division of Urology
- Cheng-Che Chen Division of Urology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 陳冠亨 Division of Urology
- Ching-Chan Lin Division of Hematology & Oncology
- Che-Hung Lin Division of Hematology & Oncology
- Yi-Huei Chang Division of Urology
- Po-Jen Hsiao Division of Urology
- Su-Peng Yeh Division of Hematology & Oncology
- Chi-Ping Huang Division of Urology
- Chi-Rei Yang Division of Urology
- Hsi-Chin Wu Division of Urology
- Wei-Ching Lin Division of Urology
- Po-Fan Hsieh Division of Urology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- - - Division of Urology
- Ying-Chun Shen Division of Hematology & Oncology
- Yeong-Shiau Pu Division of Urology
- CHUNG-HSIN CHEN Division of Urology
- YU-CHUAN LU Division of Urology
- JHE-CYUAN GUO Division of Hematology & Oncology
- - - Division of Urology
- Chia-Chi Lin Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Condition/Disease
Renal Cell Carcinoma
Objectives
Primary Objective
To assess whether a starting dose of lenvatinib 14 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).
Secondary Objectives
To assess progression-free survival (PFS).
To assess ORR.
To determine the tolerability and safety profile of lenvatinib in combination with everolimus.
To assess the proportion of subjects who discontinued treatment due to toxicity.
To assess time to treatment failure due to toxicity.
To assess pharmacokinetic (PK) profiles of lenvatinib and everolimus during
combination therapy and to assess PK and pharmacodynamic (PD) drug-drug
interactions.
To evaluate overall survival (OS).
To evaluate the impact of disease and treatment on patients' Health-Related Quality of Life
(HRQoL) as assessed by using the Functional Assessment of Cancer Therapy Kidney
Syndrome Index-Disease-Related Symptoms (FKSI-DRS), the European Organization for the
Research and Treatment of Cancer (EORTC) QLQ-C30 and the European Quality of Life
(EuroQol) EQ-5D-3L.
To evaluate the PFS after next line of treatment (PFS2).
Exploratory Objectives
To explore blood biomarkers that correlate with efficacy-related endpoints of this study.
To develop exposure/biomarker/clinical endpoint models (whenever possible, using a
mechanism-based approach) for both efficacy and safety data that will allow exploration
of alternative dosing regimens with a better efficacy/safety profile than the lenvatinib
18-mg plus everolimus 5-mg dose.
Test Drug
Lenvima Capsules 4 mg, 10 mg
Active Ingredient
Lenvatinib
Dosage Form
capsule
Dosage
4 mg, 10 mg
Endpoints
Primary Endpoints
Objective response rate (ORR) at Week 24 (ORR24W) as assessed by the investigator according to
RECIST 1.1. ORR24W is defined as the proportion of subjects with best overall response (BOR)
of complete response (CR) or partial response (PR) at the Week24 (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.
Proportion of subjects with intolerable Grade 2 and any ≥ Grade 3 TEAEs within 24 weeks after
randomization (as of the Week-24 time point).
Secondary Endpoints
Progression-free survival (PFS), defined as the time from the date of randomization to the date of
first documentation of disease progression or date of death, whichever occurs first. PFS
censoring rules will be defined in the statistical analysis plan (SAP) and will follow FDA
guidance.
ORR as assessed by the investigator according to RECIST 1.1 at the end of treatment. ORR is
defined as the proportion of subjects with BOR of CR or PR at the end of treatment. To be
considered BOR, all responses must be confirmed no less than 4 weeks after the initial
assessment of response.
Overall safety profile and tolerability of lenvatinib in combination with everolimus.
Proportion of subjects who discontinue treatment due to toxicity, defined as the proportion of
subjects who discontinue study treatment due to TEAEs.
Time to treatment failure due to toxicity, defined as the time from the date of randomization to
the date that a subject discontinues study treatment due to TEAEs.
Lenvatinib and everolimus exposure parameters and PK and PD drug-drug interactions.
Overall survival (OS), measured from the date of randomization until date of death from any
cause. In the absence of confirmation of death, subjects will be censored either at the date that
the subject was last known to be alive or the date of data cutoff, whichever comes earlier.
Health-Related Quality of Life (HRQoL) will be assessed using the Functional Assessment of
Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS), the European
Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and the European
Quality of Life (EuroQol) EQ-5D-3L instruments.
PFS2, defined as the time from randomization to the date of disease progression after next line of
therapy or death from any cause, whichever occurs first. PFS2 censoring rules will be defined in
the SAP.
Exploratory Endpoints
Associations between blood biomarker and efficacy-related endpoints.
Development of exposure/biomarker/clinical endpoint models (whenever possible, using a
mechanism-based approach) for both efficacy and safety data.
Objective response rate (ORR) at Week 24 (ORR24W) as assessed by the investigator according to
RECIST 1.1. ORR24W is defined as the proportion of subjects with best overall response (BOR)
of complete response (CR) or partial response (PR) at the Week24 (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.
Proportion of subjects with intolerable Grade 2 and any ≥ Grade 3 TEAEs within 24 weeks after
randomization (as of the Week-24 time point).
Secondary Endpoints
Progression-free survival (PFS), defined as the time from the date of randomization to the date of
first documentation of disease progression or date of death, whichever occurs first. PFS
censoring rules will be defined in the statistical analysis plan (SAP) and will follow FDA
guidance.
ORR as assessed by the investigator according to RECIST 1.1 at the end of treatment. ORR is
defined as the proportion of subjects with BOR of CR or PR at the end of treatment. To be
considered BOR, all responses must be confirmed no less than 4 weeks after the initial
assessment of response.
Overall safety profile and tolerability of lenvatinib in combination with everolimus.
Proportion of subjects who discontinue treatment due to toxicity, defined as the proportion of
subjects who discontinue study treatment due to TEAEs.
Time to treatment failure due to toxicity, defined as the time from the date of randomization to
the date that a subject discontinues study treatment due to TEAEs.
Lenvatinib and everolimus exposure parameters and PK and PD drug-drug interactions.
Overall survival (OS), measured from the date of randomization until date of death from any
cause. In the absence of confirmation of death, subjects will be censored either at the date that
the subject was last known to be alive or the date of data cutoff, whichever comes earlier.
Health-Related Quality of Life (HRQoL) will be assessed using the Functional Assessment of
Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS), the European
Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and the European
Quality of Life (EuroQol) EQ-5D-3L instruments.
PFS2, defined as the time from randomization to the date of disease progression after next line of
therapy or death from any cause, whichever occurs first. PFS2 censoring rules will be defined in
the SAP.
Exploratory Endpoints
Associations between blood biomarker and efficacy-related endpoints.
Development of exposure/biomarker/clinical endpoint models (whenever possible, using a
mechanism-based approach) for both efficacy and safety data.
Inclution Criteria
Inclusion Criteria
1. Histological or cytological confirmation of predominant clear cell RCC (original tissue diagnosis
of RCC is acceptable).
2. Documented evidence of advanced RCC.
3. One prior disease progression episode on or after 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 PD-1/PD-L1 treatment in
addition to 1 prior VEGF-targeted treatment is allowed.
4. 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 ≥1.5 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.
5. Male or female subjects 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.
6. Karnofsky Performance Status (KPS) of ≥70.
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined
as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week
before Cycle 1/Day 1.
8. Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the Cockcroft
and Gault formula (Appendix 1).
9. Adequate bone marrow function defined by:
Absolute neutrophil count (ANC) ≥1500/mm3
(≥1.5 x 109
/L)
Platelets ≥100,000/mm3
(≥100 x 109
/L)
Hemoglobin ≥9 g/dL.
10. Adequate blood coagulation function defined by International Normalized Ratio (INR) ≤1.5
(except for subjects on warfarin therapy where INR must be ≤3.0 prior to randomization).
11. Adequate liver function defined by:
Total bilirubin ≤1.5 times the 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). Subjects with bone metastases with
ALP values greater than 3 times can be included.
12. Subject must voluntarily agree to provide written informed consent.
13. Subject must be willing and able to comply with all aspects of the protocol.
1. Histological or cytological confirmation of predominant clear cell RCC (original tissue diagnosis
of RCC is acceptable).
2. Documented evidence of advanced RCC.
3. One prior disease progression episode on or after 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 PD-1/PD-L1 treatment in
addition to 1 prior VEGF-targeted treatment is allowed.
4. 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 ≥1.5 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.
5. Male or female subjects 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.
6. Karnofsky Performance Status (KPS) of ≥70.
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined
as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week
before Cycle 1/Day 1.
8. Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the Cockcroft
and Gault formula (Appendix 1).
9. Adequate bone marrow function defined by:
Absolute neutrophil count (ANC) ≥1500/mm3
(≥1.5 x 109
/L)
Platelets ≥100,000/mm3
(≥100 x 109
/L)
Hemoglobin ≥9 g/dL.
10. Adequate blood coagulation function defined by International Normalized Ratio (INR) ≤1.5
(except for subjects on warfarin therapy where INR must be ≤3.0 prior to randomization).
11. Adequate liver function defined by:
Total bilirubin ≤1.5 times the 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). Subjects with bone metastases with
ALP values greater than 3 times can be included.
12. Subject must voluntarily agree to provide written informed consent.
13. Subject must be willing and able to comply with all aspects of the protocol.
Exclusion Criteria
Exclusion Criteria
1. More than 1 prior VEGF-targeted treatment for advanced RCC.
2. Subjects 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 (eg, radiologic) or symptoms of
brain metastases must be stable for at least 4 weeks before starting study treatment.
3. 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.
4. Any anti-cancer treatment (except for radiation therapy, see exclusion #5) within 21 days, or any
investigational agent within 30 days prior to the first dose of study drug; subjects should have
recovered from any toxicity related to previous anti-cancer treatment to CTC grade 0 or 1.
5. 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.
6. 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.
7. Subjects with proteinuria >1+ on urinalysis will undergo 24-h urine collection for quantitative
assessment of proteinuria. Subjects with urine protein ≥1 g/24 h will be ineligible.
8. Fasting total cholesterol ˃300 mg/dL (or ˃7.75 mmol/L) and/or fasting triglycerides level ˃2.5 x
ULN. NOTE: these subjects can be included after initiation or adjustment of lipid-lowering
medication.
9. Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. NOTE: these subjects
can be included after initiation or adjustment of glucose-lowering medication.
10. Prolongation of QTc interval to >480 ms.
11. Subjects who have not recovered adequately from any toxicity and/or complications from major
surgery prior to starting therapy.
12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might
affect the absorption of lenvatinib or everolimus.
13. Bleeding or thrombotic disorders or subjects 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.
14. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study
drug.
15. 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.
16. Active infection (any infection requiring systemic treatment).
17. Any medical or other condition that in the opinion of the investigator(s) would preclude the
subject’s participation in a clinical study.
18. 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.
19. Females of childbearing potential* who:
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)
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 subject, then the subject 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.
NOTES:
*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].
**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.
1. More than 1 prior VEGF-targeted treatment for advanced RCC.
2. Subjects 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 (eg, radiologic) or symptoms of
brain metastases must be stable for at least 4 weeks before starting study treatment.
3. 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.
4. Any anti-cancer treatment (except for radiation therapy, see exclusion #5) within 21 days, or any
investigational agent within 30 days prior to the first dose of study drug; subjects should have
recovered from any toxicity related to previous anti-cancer treatment to CTC grade 0 or 1.
5. 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.
6. 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.
7. Subjects with proteinuria >1+ on urinalysis will undergo 24-h urine collection for quantitative
assessment of proteinuria. Subjects with urine protein ≥1 g/24 h will be ineligible.
8. Fasting total cholesterol ˃300 mg/dL (or ˃7.75 mmol/L) and/or fasting triglycerides level ˃2.5 x
ULN. NOTE: these subjects can be included after initiation or adjustment of lipid-lowering
medication.
9. Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. NOTE: these subjects
can be included after initiation or adjustment of glucose-lowering medication.
10. Prolongation of QTc interval to >480 ms.
11. Subjects who have not recovered adequately from any toxicity and/or complications from major
surgery prior to starting therapy.
12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might
affect the absorption of lenvatinib or everolimus.
13. Bleeding or thrombotic disorders or subjects 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.
14. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study
drug.
15. 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.
16. Active infection (any infection requiring systemic treatment).
17. Any medical or other condition that in the opinion of the investigator(s) would preclude the
subject’s participation in a clinical study.
18. 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.
19. Females of childbearing potential* who:
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)
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 subject, then the subject 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.
NOTES:
*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].
**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.
The Estimated Number of Participants
-
Taiwan
20 participants
-
Global
338 participants
