A Phase II, open-label study to assess the safety and efficacy of oral MEK162 in adults with locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600 or NRAS mutations

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 31

Inclusion Criteria

1. Male or female patients age >= 18 years
2. Histologically confirmed diagnosis of locally advanced or metastatic cutaneous melanoma AJCC Stage IIIB to IV, not potentially curable with surgery
3. Must have documented presence of somatic BRAFV600 or NRAS mutation in tumor tissue
4. All patients enrolled should provide sufficient fresh or archival tumor sample at baseline to enable central confirmation of BRAF or NRAS mutations and the additional analyses described in the protocol
5. Evidence of measurable tumor disease as per RECIST
6. WHO performance status of 0-2
7. Adequate organ function and laboratory parameters:
•ANC >= 1.5 x 109/L
•Hemoglobin (Hgb) >= 10 g/dL
•Platelets (PLT) >= 75 x 109/L
•AST and/or ALT <= 2.5 × upper limit of normal (ULN); patients with liver metastases <= 5 ×ULN
•Bilirubin <= 2 × ULN
•Calculated or directly measured creatinine clearance >= 60 mL/min/1.73m2
8. LVEF >= 50% as determined by MUGA scan or TTE

Exclusion Criteria

1. History or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or ophthalmopathy visible at screening that would be considered a risk factor for CSR or RVO
2. Patients with symptomatic CNS metastasis.
3. Prior therapy with a MEK- inhibitor
4. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
• History/evidence of acute coronary syndromes (including MI, unstable angina, CABG, coronary angioplasty, or stenting) <6 months prior to screening
• Symptomatic CHF, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality
• Uncontrolled arterial hypertension, defined as BP > 140/100 mmHg
5. Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection
6. Any other condition that would, in the Investigator*s judgment, contraindicate patient*s participation in the clinical study due to safety concerns or compliance with clinical study procedures , e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc.
7. Patients who have received prior systemic anti-cancer treatment within the following time frames:
•Patients who have received cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to starting study drugs
•Patients who have received biologic therapy (e.g., antibodies) within 4 weeks prior to starting study drug
•Patients who have been treated with continuous or intermittent small molecule therapeutics within <= 5 t1/2 of the agent, or <= 4 weeks prior to starting study drug where half life is unknown
•Patients who have received any other investigational agents within a period of time that is less than the cycle length used for that treatment or <= 4 weeks (whichever is shorter) prior to starting study drugs
•Treatment with prior radiotherapy within 28 days of the first dose of study drug; however, if the radiation portal covered <= 10% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
8.Patients who have undergone major surgery <= 4 weeks prior to starting study drug or who have not recovered from side effects of such procedure
9.Pregnant or nursing (lactating) women.
10.Women may not become pregnant. Reliable contraception should be maintained throughout the study and for 3 months after study drug discontinuation

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>To estimate the objective response rate (ORRs) of MEK162 in adult patients with<br /><br>advanced, unresectable, cutaneous malignant melanoma, i) harboring BARFV600 of<br /><br>ii) harboring NRAS mutations</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>* To assess the effect of oral MEK162 on time-related efficacy parameters<br /><br>(progression free survival (PFS) and duration of response)<br /><br>* To characterize the safety and tolerability of oral MEK162<br /><br>* To assess the effect of MEK162 on MEK/MAPK signaling, (PD changes of<br /><br>molecular status of ERK, DUSP6, MEK) in pre- vs. post-dose tumor biopsies<br /><br>* To characterize the baseline status of molecules relevant to MEK/MAPK<br /><br>signaling (PTEN, p53) in tumor tissue and potential correlation with clinical<br /><br>outcomes<br /><br>* To measure plasma concentrations of MEK162 and the pharmacologically active<br /><br>metabolite, AR00426032</p><br>