Unresectable Advanced or Metastatic Renal Cell Carcinoma MedDRA version: 16.1 Level: PT Classification code 10038414 Term: Renal cell carcinoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 16.1 Level: PT Classification code 10050513 Term: Metastatic renal cell carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Eisai Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
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 [ß-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 1
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: • 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.;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 i | — |
Secondary
| Measure | Time frame |
|---|---|
| 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).;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. | — |
Countries
Czech Republic, Poland, Spain, United Kingdom, United States
Contacts
Public ContactMedical Information
Eisai Ltd
Outcome results
None listed