Trametinib in Treating Patients With Advanced Melanoma With BRAF Non-V600 Mutations

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the clinical efficacy of trametinib in advanced BRAF nonV600mutation (MUT) melanoma (high activity group). SECONDARY OBJECTIVES: I. To characterize the safety of trametinib. II. To evaluate the progression-free survival (PFS) and overall survival (OS) of trametinib in advanced BRAF nonV600MUT melanoma. TERTIARY OBJECTIVES: I. To determine the clinical efficacy of trametinib in advanced BRAF nonV600MUT melanoma (low activity/unknown group). II. Identify mechanisms of resistance to trametinib in this patient population. OUTLINE: Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 28 days.

Official Title
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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

Conditions
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Recurrent Melanoma, Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Drug: trametinib
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (trametinib)<br>Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: trametinib<br>* Given PO<br>* Other names: Mekinist;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate in High Affinity Group | Per RECIST criteria version (v.) 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival All Patients | Progression of disease as defined by RECIST 1.1 criteria will be reported. Time from on treatment to progression or death (whichever comes first). For those did not progress or die, they were censored at the last follow up or off study date(if they do not have a last date of follow up). | On-study date to lesser of date of progression or date of death from any cause (assessed up to 3 years) | 
| Duration of Response in High Affinity Group | Estimated probable duration from date of objective response to date of disease progression, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as >= 20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions. | Date of first partial or complete response as defined by RECIST 1.1 criteria to date of progression up to 3 years | 
| Clinical Benefit (Complete Response [CR] + Partial Response [PR] + Stable Disease [SD]) Per RECIST v. 1.1 in High Affinity Group | Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions. | Up to 12 months | 
| Overall Survival | Estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method with censoring. | On-study date to date of death from any cause (assessed up to 3 years) | 
| Number of Patients With Each Worst-Grade Toxicity | Safety profile shown by count of patients according to the worst-grade toxicity experienced by each, where worst-grade toxicity is per National Cancer Institute (NCI) common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death. | On-study date to 30 days following final dose of study drug, up to 3 years | 
| Overall Response Rate in Low Affinity Group | Per RECIST criteria v. 1.1: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions. | Up to 12 months |