An Open-Label, 2-Cohort, Multicenter, Phase 2 Study of Levatinib in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma
Rodabe N. Amaria
The goal of this clinical research study is to learn if Lenvatinib can help to control advanced melanoma that has not responded to treatment. The safety of the study drug will also be studied.
Disease Group: Melanoma
Treatment Agent: E7080
Treatment Location: Both at MD Anderson & Other Sites
Primary: To assess the objective response rate (ORR complete response + partial response [CR + PR]) of Levatinib in subjects with unresectable stage III or stage IV melanoma not harboring the V600E BRAF mutation and who have disease progression following up to two prior systemic anticancer regimen treatments (including immunotherapies, but excluding anti-VEGF) for unresectable stage III or stage IV melanoma (Cohort 1). To assess the ORR of Levatinib in subjects with unresectable stage III or stage IV melanoma harboring the activating BRAF mutations (mainly the V600E mutation) and disease progression following BRAF-V600E-targeted therapy (Cohort 2). Secondary: To assess the progression-free survival (PFS) and overall survival (OS) of subjects in this study population treated with Levatinib (Cohorts 1 and 2). To assess the disease control rate (DCR CR + PR + stable disease [SD >/=7 weeks]) clinical benefit rate (CBR CR + PR + durable SD rate) and durable SD rate (SD >/=23 weeks) for subjects treated with Levatinib (Cohorts 1 and 2). To assess the safety and tolerability of Levatinib (Cohorts 1 and 2). To assess the pharmacokinetic (PK) profile and pharmacodynamics of Levatinib in subjects with unresectable stage III or stage IV melanoma (Cohorts 1 and 2). Exploratory: To identify and evaluate blood and tumor biomarkers (including those based on messenger ribonucleic acid [mRNA] and microRNA [miRNA] expression, deoxyribonucleic acid [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 Levatinib absorption, distribution, metabolism, and excretion (ADME). To compare the ORR between Cohort 1 and Cohort 2.
IRB Review and Approval Date: 12/13/2010
Recruitment Status: Not Accepting
Projected Accrual: 178
1) Histologically confirmed diagnosis of melanoma.
2) AJCC unresectable stage III or stage IV melanoma
3) Subjects must fall into one of two cohorts: Cohort 1: subjects have melanoma not harboring the V600E BRAF mutation (other uncommon BRAF activating mutations are allowed) - subjects have not received BRAF targeted therapy, and have disease progression following up to two prior systemic anticancer regimen treatments (including immunotherapies but excluding anti-VEGF) for unresectable stage II or stage IV disease.
4) #3 contd. Cohort 2: subjects have melanoma harboring the V600E BRAF mutation or any other activating BRAF mutations - subjects have disease progression following BRAF-V600E-targeting therapy - in addition to BRAF-V600E-targeted therapy, subjects may have received up to two prior systemic anticancer regimen treatments (including immunotherapies but excluding anti-VEGF), for unrectable stage III or stage IV disease.
5) Radiographic/photographic evidence of disease progression according to modified RECIST 1.1 following up to two prior systemic anticancer regimen treatments, including immunotherapies (Cohort 1) or up to two prior systemic anticancer regimen treatments, including immunotherapies, in addition to a BRAF-V600E-targeted therapy (Cohort 2) for unresectable stage III or stage IV disease
6) Measurable disease meeting the following criteria: At least 1 lesion of >/=1.0 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) or photography. If there is only one target lesion, it should have a longest diameter of >/= 1.5 cm (for a non-lymph node) or >/= 1.5 cm in the short-axis diamter (for a lymph node). 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.
7) ECOG performance status of 0 or 1
8) 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
9) Adequate renal function defined as calculated creatinine clearance >/=30 mL/min per the Cockcroft and Gault formula
10) Adequate bone marrow function: Absolute neutrophil count (ANC) >/=1000/mm^3 (>/=1.0 x 10^3/u/L); Platelets >/= 100,000/mm^3 (>/=100 x 10^9/L); Hemoglobin >/= 9.0 g/dL.
11) Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) </=1.5
12) 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).
13) Males or females age >/=18 years at the time of informed consent
14) All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin [beta-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 having a vasectomised partner with confirmed azoospermia must agree to use two highly effective methods of contraception: e.g.k 1) an intaurine systems (IUS) 2) a barrier method such as a condom or occlusive cup (diaphragm or cervical/vault caps) + spermicide (foam gel, grea, etc.); 3) oral injected, or implanted hormonal contracpetives 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.
15) Male subjects who are partners of women of childbearing potential must use a condom + spermicide and their female partners if of childbearing potential must use a highly efffective method of contraception beginning at lease one menstral cycle prior to starting the study drug, throughout the entire studyperiod and for 30 days after the last dose of study drug, unless the male subjects are totally abstinent sexually or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile.
16) Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol
17) Subjects with brain metastases will be eligible under the following conditions a) have undergone complete surgical excision and are more than 1 month post surgery with no radiographic evidence of disease recurrence in the brain, or b) have undergone stereotactic radio surgery (gamma knife procedure) and are more than 1 month post procedure and with no radiographic evidence of disease progression in the brain, and c) are asymptomatic, and d) discontinued corticosteroid treatment at least 30 days prior to Cycle 1, Day 1
1) Melanoma of intraocular origin
2) Leptomeningeal metastases or brain metastases except as for Inclusion Criterion #6
3) More than two prior systemic anticancer regimen treatments including immunotherapies 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 or subjects who received in the past more than two prior sytemic anticancer regimen treatments, including immunotherapies, in addition to a BRAF-V600E-targeted therapy. There is no restriction regarding prior adjuvant treatment (Cohort 2). Drugs to be excluded include: bevacizumab, axitinib, motesanib, pazopanib, sorafenib, sunitinib, vandetanib, vatalanib, ABT-869, BIBF1120, Cediranib, CHIR-258, RAF-265, LX880, XL-184 among others. BRAF inhibitors include (PLX4032/RO5185426, GSK2118436, RAF265 and XL281)
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 Levatinib treatment as soon as 14 days following the last dose of the BRAF targeted therapy.
6) Subjects having >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 Levatinib
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; 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
Information and next steps
Rodabe N. Amaria
Melanoma Medical Oncology
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