| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced renal cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| kidney cancer that has advanced and tumours are getting bigger |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038389 |
| E.1.2 | Term | Renal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038409 |
| E.1.2 | Term | Renal cell carcinoma NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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). |
|
| E.2.2 | Secondary objectives of the trial |
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). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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 or left ventricular ejection fraction (LVEF) below the institutional normal range as determined by screening multiple- gated acquisition (MUGA) scan or echocardiogram.
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 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)
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Objective response rate 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 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.
Proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks after randomization (as of the Week-24 time point). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Objective response rate (ORR24W) will be assessed at week-24 (after randomization) time point or earlier and at interim and final analysis.
The safety end point for the primary analyses will be assessed within 24 weeks after randomisation. |
|
| E.5.2 | Secondary end point(s) |
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, or the data of data cutoff for the primary analysis, whichever occurs first. PFS censoring rules will be defined in the statistical analysis plan (SAP) .
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, for the primary analysis, 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, or the date of data cutoff for the primary analysis, whichever occurs first. PFS2 censoring rules will be defined in the SAP |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The median survival time and the survival rates at 12 , 18 and 24 months will be assessed.
HRQoL will be assessed at 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Korea, Republic of |
| Taiwan |
| United States |
| Finland |
| Poland |
| Bulgaria |
| Netherlands |
| Romania |
| Spain |
| Czechia |
| Greece |
| Hungary |
| Portugal |
| Russian Federation |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The last subject's last assessment (Off-treatment visit) after the data cutoff for the primary analysis will be the End of Study. All subjects who are still on study treatment after the data cutoff for the primary analysis (ie, at the end of the Randomization Phase) will continue to receive investigational product untill they complete the Off-Treatment Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
Print
