| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable Advanced or Metastatic Renal Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced kidney cancer which 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038414 |
| E.1.2 | Term | Renal cell carcinoma stage IV |
| 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 | 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase Ib: To determine the dose limiting toxicities and maximally tolerated dose and establish the recommended phase 2 (RP2) dose for E7080 incombination with everolimus in subjects with unresectable advanced or metastatic renal cell carcinoma (RCC).
Phase 2: To compare the progression free survival of 1) E7080 in combination with everolimus at the RP2 dose once daily (Arm A) and 2) single agent E7080 24 mg once daily (Arm B) to single agent everolimus 10 mg once daily (Arm C) in subjects with unresectable advanced or metastatic RCC and disease progression following one prior VEGF targeted treatment. |
|
| E.2.2 | Secondary objectives of the trial |
• Phase 1b & 2: To determine the tolerability and safety profile of E7080 in combination with everolimus and (Phase 2 only) of E7080 alone
• Phase 2: To compare PFS of Arm A, E7080-everolimus to Arm B, E7080
• Phase 2: To assess overall survival (OS)
• Phase 2: To assess objective response rate (ORR: CR + PR); disease control rate (DCR: CR + PR + SD]; durable SD (SD = 23 weeks) and clinical benefit rate (CBR: CR, PR + durable SD).
• Phase 2: To assess PK profiles (eg, AUC, Cmax) of E7080 and
everolimus during single agent and combination therapy.
• Phase 1b & 2: To assess PK and PD relationship of E7080 as single agent (Phase 2 only) and combination therapy.
EXPLORATORY OBJECTIVE(S)
• Phase 1b: To assess the BOR
• Phase 2: To identify and explore blood and tumor biomarkers which correlate with
efficacy-related endpoints of this study.
• Phase 2: To evaluate role of DNA sequence variability on ADME and susceptibility to adverse events of E7080. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Histologically confirmed diagnosis of renal cell carcinoma. 2) Phase 1: Disease progression after prior vascular endothelial growth factor (VEGF)-targeted treatment. 3) Phase 2: Histological or cytological confirmation of predominant clear cell RCC (original tissue diagnosis of RCC is acceptable). 4) Documented evidence of unresectable advanced or metastatic RCC. 5) Phase 2: Radiographic evidence of disease progression according to RECIST 1.1 on or within 9 months of stopping prior therapy. 6) Phase 2: One prior disease
progression episode on or after vascular endothelial growth factor (VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, bevacizumab, axitinib, vatalanib, AV951/ tivozanib) for unresectable advanced or metastatic RCC (not including disease progression after VEGF-targeted adjuvant treatment). 7) Phase 2: Measurable disease meeting the following criteria:
a) At least 1 lesion of ≥ 1.5 cm in the longest diameter for a non-lymph node or ≥ 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computerized tomography /magnetic resonance imaging (CT/MRI) or photography b) Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion
8) Subjects must have an ECOG Performance Status of 0 or 1.
9) Adequately controlled blood pressure with or without antihypertensive medications, defined as BP ≤ 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1 10) Adequate renal function defined as calculated creatinine clearance ≥ 30 mL/min. 11) Adequate bone marrow function:
− Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 x 103/μL);
− Platelets ≥ 100,000/mm3 (≥ 100 x 109/L);
− Hemoglobin ≥ 9.0 g/dL.
12) Adequate blood coagulation function 13) Adequate liver function:
− Bilirubin ≤ 1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinaemia of Gilbert’s syndrome;
− Alkaline phosphatase, alanine aminotransferase (ALT), and aspartateaminotransferase (AST) ≤ 3 times ULN (≤ 5 x ULN if subject has liver metastases). 14) Males or females age ≥ 18 years at the time of informed consent. 15) All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin [β-hCG]) at the Screening Visit (and/or within 72 hours of the first dose of study drug). Females of child-bearing potential, if not practicing total abstinence or have a vasectomised partner with confirmed azoospermia, must agree to use two highly effective methods of contraception ( e.g., 1), abstinence, an intrauterine device [IUD], or intrauterine system (IUS); 2) a barrier method such as condom or occlusive cup (diaphragm or cervical/vault caps) + spermicide (foam, gel, cream, etc.) 3) oral, injected, or implanted hormonal contraceptives throughout the entire study period and for 30 days after study drug discontinuation. Use of a double-barrier method (i.e., use at the same time of a condom + occlusive cup [diaphragm or cervical/vault caps] + spermicide [foam, gel, cream, etc.]) is accepted as two highly effective methods of contraception. The only subjects who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or subjects who have been sterilized surgically or who are otherwise proven sterile (ie, bilateral tubal ligation with surgery at least 1 month prior to dosing, total hysterectomy, or bilateral oophorectomy with surgery at least 1 month prior to dosing). All women who are of reproductive potential and who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. 16) Male subjects who are partners of women of childbearing potential must use a highly effective method of contraception eg., a condom + spermicide and their female partners if of childbearing potential must use a highly effective method of contraception (see methods described in Inclusion Criterion #15) beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 30 days after the last dose of study drug, unless they are the male subjects are totally sexually abstinent or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile 17) Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol. |
|
| E.4 | Principal exclusion criteria |
1) Phase 1b or Phase 2 specific per below:
− Phase 1b only: Subjects with untreated or unstable metastases to the CNS are excluded. Subjects who have completed local therapy and have discontinued the use of steroids for this indication at least 4 weeks prior to commencing treatment
and in whom stability has been proven by at least 2 CT or MRI scans obtained at least 4 weeks apart are eligible for Phase 1b only.
− Phase 2 only: subjects with CNS (eg, brain or leptomeningeal) metastases are excluded.
2) Phase 2 only: More than one prior disease progression episode on or after VEGF-targeted treatment for unresectable advanced or metastatic RCC (not including
disease progression after VEGF-targeted
adjuvant treatment).
3) Phase 1b or Phase 2 specific per below:
− Phase 1b only: Prior exposure to E7080
− Phase 2 only: Prior exposure to E7080 or mTOR inhibitor
4) Subjects should not have received any anti-cancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug and should have recovered from any toxicity related to previous anti-cancer treatment.
5) Major surgery within 3 weeks prior to the first dose of study drug
6) Subjects having > 1+ proteinuria on urinalysis will undergo 24-h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥ 1 g/24-hour will be ineligible.
7) Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN.
8) Fasting total cholesterol > 7.75 mmol/L (>300 mg/dl).
9) Fasting triglyceride level > 2.5 x ULN.
10) Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of E7080 or everolimus.
11) Significant cardiovascular impairment: history of congestive heart failure greater than New York heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment.
12) Prolongation of QTc interval to > 480 msec.
13) Bleeding disorder or thrombotic disorder requiring anticoagulant therapy, such as warfarin, or similar agents requiring therapeutic international normalized ratio (INR) monitoring (treatment with low molecular weight heparin [LMWH] is allowed).
14) Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
15) Active infection (any infection requiring treatment).
16) Phase 2 only: Active malignancy (except for renal cell carcinoma, melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
17) Known intolerance to any of the study drugs (or any of the excipients) and/or known hypersensitivity to rapamycins (eg, sirolimus, everolimus, temsirolimus) or any of the excipients.
18) Phase 1b only: Subjects who discontinued prior tyrosine kinase inhibitor due to toxicity will be ineligible.
19) Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.
20) Females who are pregnant or breastfeeding.
21) Medical need for the continued use of potent inhibitors of CYP3A4. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of Phase 1b is to determine the DLTs, MTD and establish the recommended dose for Phase 2.
For Phase 2, the primary efficacy endpoint is Progression-free Survival (PFS) and is defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurs first). The primary PFS will be based on investigator review data
using RECIST 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The Phase 2 primary analysis will be performed at the end of the randomization phase (ie, when a total of at least 90 PFS events among 3 treatment arms and at least 60 PFS events among Arm A (or Arm B) and Arm C have been observed in the Phase 2 part of the study). |
|
| E.5.2 | Secondary end point(s) |
| The secondary efficacy endpoints are Overall Survival, objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and durable SD (SD ≥ 23 weeks). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of the randomization phase, primary and secondary endpoints will be evaluated. Except that at the end of the randomization phase, there might be not enough OS events. So, the primary analysis of OS will be performed at the follow-up analysis during the extension phase. Median survival time and the cumulative probability of survival at 12, 18 and 24 months will be calculated. |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| sequential cohort dose escalation |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Czech Republic |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| Last subject, last 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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