| 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 spread to other parts of the body |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| 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 |
| The primary objective of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progression-free survival (PFS) (by independent imaging review [IIR] using Response Evaluation Criteria In Solid Tumors [RECIST 1.1]) as first-line treatment in subjects with advanced renal cell carcinoma (RCC). |
|
| E.2.2 | Secondary objectives of the trial |
•To compare objective response rate (ORR) of subjects treated with lenvatinib in combination with everolimus or pembrolizumab versus sunitinib.
•To compare overall survival (OS) of subjects treated with lenvatinib in combination with everolimus or pembrolizumab versus sunitinib.
•To compare safety and tolerability of treatment with lenvatinib in combination with everolimus or pembrolizumab versus sunitinib.
•To compare the impact of treatment on Health-Related Quality of Life
•To assess PFS on next-line of therapy (PFS2)
• To assess PFS based on investigator assessment per RECIST v.1.1
• To characterize the population pharmacokinetics (PK) of lenvatinib when co-administered with everolimus or pembrolizumab.
• To characterize the population PK of everolimus and pembrolizumab when co-administered with lenvatinib.
• To assess the PK/pharmacodynamic relationship between exposure and efficacy/biomarkers/safety. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological or cytological confirmation of RCC with a clear-cell component (original tissue diagnosis of RCC is acceptable).
2. Documented evidence of advanced RCC.
3. 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.
4. Male or female subjects age ≥18 years (or any age greater than 18 years of age if that age is considered to be an adult per the local jurisdiction) at the time of informed consent
5. Karnofsky Performance Status (KPS) of ≥70.
6. 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 the Cycle 1/Day 1.
7. Adequate renal function as creatinine ≤1.5× upper limit of normal
(ULN); or for subjects with creatinine >1.5×ULN, the calculated
creatinine clearance ≥30 mL/min (per the Cockcroft-Gault formula) is
acceptable.
8.Adequate bone marrow function defined by:
•Absolute neutrophil count (ANC) ≥1500/mm3
•Platelets ≥100,000/mm3
•Hemoglobin ≥9 g/dL
NOTE: Criteria must be met without erythropoietin dependency and
without packed red blood cell (pRBC) transfusion within the previous 2
weeks.
9.Adequate blood coagulation function defined by International
Normalized ratio (INR) ≤1.5 unless participant is receiving anticoagulant
therapy, as long as INR is within therapeutic range of intended use of
anticoagulants.
10.Adequate liver function defined by:
•Total bilirubin ≤1.5×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), unless there are bone metastases. Subjects with
ALP values >3×ULN and known to have bone metastases can be
included.
11. Provide written informed consent.
12. Willing and able to comply with all aspects of the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Subj. who have received any systemic anticancer therapy for RCC,
including anti-VEGF therapy, or any systemic investigational anticancer
agent. Prior adjuvant treatment with an investigational anticancer agent
is not allowed unless the investigator can provide evidence of subject's
randomization to placebo arm.
2. Subj. with CNS metastases are not eligible, unless they have
completed local therapy (eg, whole brain radiation therapy [WBRT],
surgery or radiosurgery) and have discontinued the use of
corticosteroids for this indication for at least 4 weeks before starting
treatment in this study.
3. Active malignancy (ex. for RCC, definitively treated basal or squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix
or bladder) within the past 24 months. Subjects with history of localized
& low risk prostate cancer are allowed in the study if they were treated
with curative intent if no PSA recurrence within the past 5 years.
4. 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.
5. Subj. who are using other investigational agents or who had
received investigational drugs ≤4 weeks prior to study treatment start.
6. Received a live vaccine within 30 days of planned start of study
treatment (Cycle 1/Day 1). Examples of live vaccines include, measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,
Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal
influenza vaccines for injection are generally killed virus vaccines and
are allowed; however, intranasal influenza vaccines (eg, FluMist®) are
live attenuated vaccines and are not allowed.
7. Subj. with proteinuria >1+ on urine dipstick testing will undergo
24-h urine collection for quantitative assessment of proteinuria.
Subj. 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. Subj.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,
everolimus, and/or sunitinib.
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 signif. hemoptysis or tumor bleeding within 2 weeks
prior to the first dose of study drug.
15. Signif. cardiovascular impairment within 12 months of the first
dose of study drug: history of congestive heart failure greater than New
York Heart Association (NYHA) Class II, unstable angina, myocardial
infarction, cerebrovascular accident (CVA), or cardiac arrhythmia
associated with hemodynamic instability.
The following is also excluded:
•Left ventricular ejection fraction (LVEF) below the institutional normal
range as determined by MUGA or echocardiogram.
16. Active infection (any infection requiring systemic treatment).
17. Subjects known to be positive for Human Immunodeficiency Virus
(HIV). 18. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg,
HCV RNA [qualitative] is detected).
19. Known history of, or any evidence of, interstitial lung disease.
20.Has a history of (non-infectious) pneumonitis that required steroids,
or current pneumonitis
21. Any medical or other condition that in the opinion of the
investigator(s) would preclude the subject's participation in a clinical
study.
22. Subjects with a diagnosis of immunodeficiency or who are receiving
chronic systemic steroid therapy or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study
treatment.
23. Active autoimmune disease (with the exception of psoriasis) that has
required systemic treatment in the past 2 years.
24. Females who are breastfeeding or pregnant at Screening or Baseline.
25. Females of childbearing potential who do not agree to use a highly
effective method of contraception for the entire study period and for 120
days after study discontinuation.
26. Males who have not had a successful vasectomy and do not agree to
use condom + spermicide OR have a female partner who does not meet
the criteria above.
27. Known intolerance to any of the study drugs (or any of the
excipients). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Progression-free survival (PFS) by independent review is defined as the time from the date of randomization to the date of the first documentation of disease progression or death (whichever occurs first) as determined by IIR using RECIST 1.1. PFS censoring rules will follow the FDA guidance of 2007; specifics of this will be detailed in the Statistical Analysis Plan. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
An interim and a final analysis of PFS (as determined by the IIR) are planned to be performed. Assuming an average enrollment rate of 31 subjects per month, the interim and final analysis of PFS will occur approximately 38 and 45 months (34 month enrollment period) after the first subject is randomized. A total of 582 PFS events are expected in 3 arms by the time of the planned final PFS
analysis. |
|
| E.5.2 | Secondary end point(s) |
• Objective response rate (ORR) is defined as the proportion of subjects who have best overall response of CR or PR as determined by IIR using RECIST 1.1.
• Overall survival (OS) is defined as the time from the date of randomization to the date of death from any cause. Subjects who are lost to follow-up and those who are alive at the date of data cut-off will be censored at the date the subject was last known alive, or date of data cut-off, whichever occurs first.
• Safety will be assessed summarizing the incidence of treatment-emergent adverse events (TEAEs) and SAEs together with all other safety parameters.
• Proportion of subjects who discontinued treatment due to toxicity is defined as the proportion of subjects who discontinue study treatment due to treatment-emergent adverse events (TEAEs).
• Time to treatment failure due to toxicity is defined as the time from the date of first dose to the date that a subject discontinues study treatment due to TEAEs.
• Health-Related Quality of Life (HRQoL) will be assessed using the Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptom (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.
• PFS on next-line of therapy (PFS2) is defined as the time from randomization to disease progression on next-line of treatment, or death from any cause, (whichever occurs first).
• Progression-free survival (PFS) by investigator assessment is defined as the time from the date of randomization to the date of first documentation of disease progression based on the investigator assessment per RECIST v.1.1 or death (whichever occurs first).
• Model-predicted clearance and AUC for lenvatinib in Arms A and B.
• Model-predicted clearance and AUC for everolimus in Arm A, and pembrolizumab in Arm B. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
| Japan |
| United States |
| Switzerland |
| Russian Federation |
| Korea, Republic of |
|
| 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
|
| Date of the data cutoff for the final analysis or last subject/last visit, including discontinuation from the study for any reason, whichever occurs later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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