American Joint Committee on Cancer unresectable stage III or stage IV melanima and disease progression with subjects not harboring the V600E-BRAF mutation with disease progression following first line standard of care (cohort 1) or subjects harboring the V600E-BRAF mutation with disease progression following BRAF-V600E-targeted therapy (cohort 2). MedDRA version: 14.1 Level: PT Classification code 10025650 Term: Malignant melanoma System Organ Class: 10029104 - Neoplasms benign, malignant and u
Conditions
Interventions
Product Name: E7080
Product Code: E7080
Pharmaceutical Form: Capsule, hard
Current Sponsor code: E7080
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-
Product N
Sponsors
Eisai Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed diagnosis of melanoma. 2. AJCC unresectable stage III or stage IV melanoma (Appendix 1). 3. Melanoma not harboring the V600E BRAF mutation (Cohort 1) and melanoma harboring the V600E BRAF mutation (Cohort 2). 4. Radiographic/photographic evidence of disease progression according to modified RECIST 1.1 (Appendix 2) following first-line standard of care therapy (Cohort 1) or BRAF-V600E-targeted therapy (Cohort 2) for unresectable stage III or stage IV disease. 5. Measurable disease meeting the following criteria: – 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 modified RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI) (see Section 8.5.1.3 Tumor Response Assessments and Appendix 2). – 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 modified RECIST 1.1 to be deemed a target lesion. 6. ECOG performance status of 0 or 1 (Appendix 3). 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 prior to the Screening Visit. 8. Adequate renal function defined as calculated creatinine clearance =30 mL/min per the Cockcroft and Gault formula (Appendix 4). 9. Adequate bone marrow function: - Absolute neutrophil count (ANC) =1000/mm3 (=1.0 x 103/micro/L); - Platelets =100,000/mm3 (=100 x 109/L); - Hemoglobin =9.0 g/dL. 10. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) <=1.5. 11. 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 aspartate aminotransferase (AST) <=3 x ULN (<=5 x ULN if subject has liver metastases). 12. Males or females age =18 years at the time of informed consent. 13. 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 must agree to use a medically acceptable method of contraception (e.g., abstinence, an intrauterine device [IUD], a double-barrier method such as condom + spermicide or condom + diaphragm with spermicide, a contraceptive implant, an oral contraceptive or have a vasectomised partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. 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 (i.e., bilateral tubal ligation with surgery at least 1 month prior to dosing, 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 leas
Exclusion criteria
Exclusion criteria: 1. Melanoma of intraocular origin. 2. Brain or leptomeningeal metastases. 3. More than 1 prior systemic chemotherapy regimen for unresectable stage III or stage IV disease or any treatment targeting vascular endothelial growth factor (VEGF)-directed angiogenesis. There is no restriction regarding prior adjuvant treatment (Cohort 1). 4. Subjects not previously treated with BRAF-V600E-targeted therapy for unresectable stage III or stage IV disease or subjects receiving any prior treatment targeting vascular endothelial growth factor (VEGF)-directed angiogenesis. There is no restriction regarding prior adjuvant treatment (Cohort 2). 5. Subjects who have received any anti-cancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug or who have not recovered from any acute toxicity related to previous anti-cancer treatment. The exception to this exclusion will be that subjects with rapid disease progression while receiving BRAF targeted therapy may begin E7080 treatment as soon as 14 days following the last dose of the BRAF targeted therapy. 6. Subjects with >1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with 24-hour urine protein =1 gm will be ineligible. 7. Inability to take oral medication, gastrointestinal malabsorption, or any other condition that might affect the absorption of E7080. 8. Major surgery within 3 weeks prior to the first dose of study drug. 9. Significant cardiovascular impairment: history or congestive heart failure greater than New York Heart Association (NYHA) Class II (Appendix 5); unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment. 10. Prolongation of QTc interval to >480 msec. 11. Bleeding disorder or a thrombotic disorder requiring anticoagulant therapy such as warfarin, or similar agents requiring therapeutic INR monitoring (treatment with low molecular weight heparin [LMWH] is allowed). 12. Active hemoptysis (bright red blood of at least ½ teaspoon) within 3 weeks prior to the first dose of study drug. 13. Active malignancy (except for melanoma, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months. 14. Females who are pregnant or breastfeeding. 15. Know intolerance to the study drug (or any of the excipients). 16. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objectives of this study are: • To assess the ORR (complete response + partial response [CR + PR]) of E7080 in subjects with unresectable stage III or stage IV melanoma not harboring the V600E BRAF mutation and disease progression following first-line standard of care therapy (Cohort 1). • To assess the ORR of E7080 in subjects with unresectable stage III or stage IV melanoma harboring the V600E BRAF mutation and disease progression following BRAF-V600E-targeted therapy (Cohort 2). ;Secondary Objective: Secondary objectives: • To assess progression-free survival and overall survival of subjects in this study population treated with E7080 (Cohorts 1 and 2). • To assess the disease control rate (DCR; CR + PR + stable disease >=7 weeks); clinical benefit rate (CBR; CR + PR + durable SD rate); and durable SD rate >=23 weeks for subjects treated with E7080 (Cohorts 1 and 2). • To assess the safety and tolerability of E7080 (Cohorts 1 and 2). • To assess the pharmacokinetic profile and pharmacodynamics of E7080 in subjects with unresectable stage III or stage IV melanoma (Cohorts 1 and 2). Exploratory objectives: • To identify and evaluate blood and tumor biomarkers (including those based on mRNA and microRNA expression, DNA sequence, and proteomic signatures) which correlate with the efficacy-related endpoints of this study. • To identify and evaluate DNA-sequence variants in genes influencing E7080 ADME. • To compare the ORR between Cohort 1 and Cohort 2.;Primary end point(s): The primary efficacy endpoint is the objective response rate defined as the proportion of subjects in each cohort who have a best overall response of CR or PR based on modified RECIST 1.1 as determined by IRR.;Timepoint(s) of evaluation of this end point: End of the treatment phase for each cohort when all enrolled subjects complete a minimum of 6 cycles of treatment (or discontinue treatment prior to completing 6 cycles). The primary analysis for the 2 cohorts will b | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoint is to assess the pfs and os of subjects, assess the disease control rate, clinical benefit rate and durable SD rate, assess safety and tolerability and assess the PK and PD of E7080 in subjects with unresectable stage III or stage IV melanoma;Timepoint(s) of evaluation of this end point: End of the treatment phase for each cohort when all enrolled subjects complete a minimum of 6 cycles of treatment (or discontinue treatment prior to completing 6 cycles). The primary analysis for the 2 cohorts will be performed separately | — |
Countries
Australia, Germany, United Kingdom, United States
Contacts
Public ContactMedical Information
Eisai Limited
Outcome results
None listed