A Phase II Open-Label, Two-Arm Study of the MEK Inhibitor, Trametinib, To Investigate the Safety and Anti-Cancer Activity in Subjects with Melanoma with BRAF non-V600 Mutations VICC MEL 1457
Some types of melanoma have a kind of BRAF mutation called a BRAFV600 mutation. A drug called trametinib is FDA approved and commercially available to treat these types of melanoma. The goal of this clinical research study is to learn if trametinib can help to control melanoma with a BRAF mutation that is not a BRAFV600 mutation. The safety of this drug will also be studied.
Disease Group: Melanoma
Treatment Agent: Trametinib
Treatment Location: Both at MDACC & and Other Sites
Sponsor: National Comprehensive Cancer Network (NCCN),Novartis,Vanderbilt-Ingram Cancer Center
Primary: To determine the clinical efficacy of trametinib in advanced BRAF nonV600MUT melanoma (“high activity” group) Secondary: To characterize the safety of trametinib To evaluate the progression-free survival (PFS) and overall survival (OS) of trametinib in advanced BRAF nonV600MUT melanoma Exploratory: To determine the clinical efficacy of trametinib in advanced BRAF nonV600MUT melanoma (“low activity/unknown” group) Identify mechanisms of resistance to trametinib in this patient population
IRB Review and Approval Date: 08/12/2015
Recruitment Status: Open
Projected Accrual: 50 patients
1) >/= 18 years old.
2) Signed written informed consent.
3) Histologically or cytologically confirmed diagnosis of melanoma.
4) BRAF mutation in loci other than V600 (BRAF nonV600 MUT) or BRAF fusion detected by genetic testing of the primary tumor or regional/distant metastasis.
5) Subjects must provide either a fresh or archived tumor sample for correlative study analyses.
6) For subjects with melanoma, archived or freshly biopsied tumor tissue (preferred) must be obtained prior to enrollment. Tissue shipment tracking information should be provided before administration of study treatment is initiated. However, if shipping will be delayed and tissue shipment tracking information is unavailable, study drug may be administered prior to tissue receipt pending discussion with principal investigator.
7) Measurable disease (i.e., present with at least one measurable lesion per RECIST, version 1.1
8) All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed) must be </= grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of randomization. Subjects with endocrinopathies (e. g. hypopituitarism, hypothyroidism; hypoadrenalism) caused by immune therapies currently on adequate hormone replacement WILL be permitted.
9) Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
10) Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception
11) Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception
12) An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
13) Adequate baseline organ function as defined: [Hematologic ANC >/= 1.0 × 10^9/L, Hemoglobin >/= 9 g/dL, Platelet count >/= 75 x 10^9/L, PT/INR^a and PTT </= 1.3 x ULN, Hepatic Albumin >/= 2.5 g/dL, Total bilirubin </= 1.5 x ULN, ALT </= 2.5 x ULN, Renal Creatinine or </= 1.5 ULN, Calculated creatinine clearance^b >/= 50 mL/min, Cardiac Left Ventricular Ejection fraction (LVEF) >/= LLN by ECHO (a.) Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization. PT and PTT > 1.5 x ULN are permitted in these subjects. (b.) Calculate creatinine clearance using standard Cockcroft-Gault formula. Creatinine clearance must be >/=50 mL/min to be eligible.]
1) No prior therapy with inhibitors affecting the MAPK pathways at any
level (BRAF, MEK, NRAS, ERK inhibitors) for unresectable stage IIIC of
Stage IV (metastatic) melanoma. No limit to other therapies
(immunotherapy or chemotherapy). Prior systemic treatment in the
adjuvant setting is allowed. (Note: Ipilimumab treatment must end at
least 8 weeks prior to Study Day 1).
2) BRAFV600 mutation positive.
3) NRAS codon 12, 13, or 61 mutation.
4) Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to Study Day 1, or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to Study Day 1.
5) Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to Study Day 1.
6) Current use of a prohibited medications
7) History of another malignancy Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected, non-melanoma skin cancer, or subjects with indolent second malignancies are eligible. T1a melanoma and melanoma in situ are permitted. Consult Medical Monitor if unsure whether second malignancies meet requirements specified above.
8) Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
9) Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
10) History of leptomeningeal disease or spinal cord compression secondary to metastasis.
11) Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery and the disease has been confirmed stable (i.e., no increase in lesion size) for at least 6 weeks with two consecutive MRI scans using contrast prior to Study Day 1 (the first MRI may be prior to surgical resection or radiation).
12) A history or evidence of cardiovascular risk including any of the following: (a.) A QT interval corrected for heart rate using the Bazett’s formula, QTc >/= 480 msec; (b.) A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for > 30 days prior to Study Day 1; (c.) History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to Study Day 1; (d.) A history or evidence of current Class I congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; (e.) Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti- hypertensive therapy; (f.) Patients with intra-cardiac defibrillators or permanent pacemakers; (g.) Known cardiac metastases;
13) A history or current evidence of RVO including: (a.) History of RVO or (b.) Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO such as: Evidence of new optic disc cupping; Evidence of new visual field defects; Intraocular pressure >21 mmHg as measured by tonography.
14) Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
15) History of interstitial lung disease or pneumonitis.
16) Females who are pregnant or nursing
Information and next steps
Melanoma Medical Oncology
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