Trametinib in Treating Patients With Advanced Melanoma With BRAF Non-V600 Mutations
Condition: Recurrent Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma
MeSH terms: Melanoma
Intervention: trametinib; laboratory biomarker analysis; pharmacological study
Intervention description: Given PO; Correlative studies; Correlative studies
Intervention MeSH terms: Trametinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies trametinib in treating patients with melanoma with v-Raf murine
      sarcoma viral oncogene homolog B (BRAF) non-V600 mutations that has spread to other places in
      the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed written informed consent

          -  Histologically or cytologically confirmed diagnosis of melanoma

          -  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

          -  Subjects must provide either a fresh or archived tumor sample for correlative study
             analyses

          -  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.

          -  Measurable disease (i.e., present with at least one measurable lesion per Response
             Evaluation Criteria In Solid Tumors [RECIST], version 1.1)

          -  All prior anti-cancer treatment-related toxicities (except alopecia and laboratory
             values) 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.

          -  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

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days prior to randomization and agree to use effective contraception

          -  Men with a female partner of childbearing potential must have either had a prior
             vasectomy or agree to use effective contraception

          -  An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Absolute neutrophil count (ANC) > or = 1.0 × 10^9/L

          -  Hemoglobin > or = 9 g/dL

          -  Platelet count > or = 75 x 10^9/L

          -  Prothrombin time (PT)/international normalized ratio (INR)* = or < 1.3 x upper limit
             of normal (ULN)

               -  Subjects receiving anticoagulation treatment may be allowed to participate with
                  INR established within the therapeutic range prior to randomization; PT and
                  partial thromboplastin time (PTT) > 1.5 x ULN are permitted in these subjects

          -  PTT =or < 1.3 x ULN

          -  Albumin >or = 2.5 g/dL

          -  Total bilirubin = or < 1.5 x ULN

          -  Alanine aminotransferase (ALT) = or < 2.5 x ULN

          -  Creatinine = or < 1.5 ULN or calculated creatinine clearance* > or = 50 mL/min

               -  Calculate creatinine clearance using standard Cockcroft-Gault formula; creatinine
                  clearance must be > or = 50 mL/min to be eligible

          -  Left ventricular ejection fraction (LVEF) > or = lower limit of normal (LLN) by
             echocardiogram (ECHO)

        Exclusion Criteria:

          -  No prior therapy with inhibitors affecting the mitogen-activated protein kinase (MAPK)
             pathways at any level (BRAF, mitogen-activated protein [MAP]/extracellular
             signal-related kinase [ERK] kinase [MEK], neuroblastoma RAS viral [v-ras] oncogene
             homolog [NRAS], ERK inhibitors) for unresectable stage IIIC or 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)

          -  BRAFV600 mutation positive

          -  NRAS codon 12, 13, or 61 mutation

          -  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

          -  Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days),
             whichever is shorter, prior to study day 1

          -  Current use of a prohibited medication as described

          -  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.

          -  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

          -  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)

          -  History of leptomeningeal disease or spinal cord compression secondary to metastasis

          -  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 magnetic resonance imaging (MRI) scans using
             contrast prior to study day 1; enzyme inducing anticonvulsants are not allowed while
             patients are on study treatment

          -  A history or evidence of cardiovascular risk including any of the following:

               -  A QT interval corrected for heart rate using the Bazett's formula (QTc) > or =
                  480 msec

               -  A history or evidence of current clinically significant uncontrolled arrhythmias

                    -  Exception: subjects with atrial fibrillation controlled for > 30 days prior
                       to study day 1

               -  History of acute coronary syndromes (including myocardial infarction and unstable
                  angina), coronary angioplasty, or stenting within 6 months prior to study day 1

               -  A history or evidence of current >= class I congestive heart failure as defined
                  by the New York Heart Association (NYHA) guidelines

               -  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

               -  Patients with intra-cardiac defibrillators or permanent pacemakers

               -  Known cardiac metastases

          -  A history or current evidence of retinal vein occlusion (RVO) including:

               -  History of RVO or

               -  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

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study treatments, their excipients, and/or dimethyl
             sulfoxide (DMSO)

          -  History of interstitial lung disease or pneumonitis

          -  Females who are pregnant or nursing