A Phase II Study of Single Agent MEK162 in Patients With Advanced Melanoma

Study Overview
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Brief Summary
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The study will assess the safety and efficacy of single-agent MEK162 in adult patients with locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600E or NRAS mutations.

Official Title
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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

Conditions
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BRAF or NRAS Mutant Metastatic Melanoma

Intervention / Treatment
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* Drug: MEK162


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced or metastatic cutaneous melanoma AJCC Stage IIIB to IV, not potentially curable with surgery BRAF or NRAS mutation in tumor tissue All patients enrolled should provide sufficient fresh or archival tumor sample at baseline to enable confirmation of BRAF or NRAS mutations and the additional analyses described in the protocol Evidence of measurable tumor disease as per RECIST WHO performance status of 0-2 Adequate organ function and laboratory parameters Exclusion Criteria: History or evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for CSR or RVO Patients with unstable CNS metastasis Prior treatment with a MEK- inhibitor Impaired cardiovascular function HIV, active Hepatitis B, and/or active Hepatitis C infection Pregnant or nursing (lactating) women Women of child-bearing potential UNLESS they comply with protocol contraceptive requirements Other protocol-defined inclusion/exclusion criteria may apply.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BRAFV600 mutant, 45mg bid MEK162<br>BRAFV600 mutant, 45mg bid MEK162 | Drug: MEK162<br> <br> |
| Experimental: NRAS mutant, 45mg bid MEK162<br>NRAS mutant, 45mg bid MEK162 | Drug: MEK162<br> <br> |
| Experimental: BRAFV600 mutant, 60mg bid MEK162<br>BRAFV600 mutant, 60mg bid MEK162 | Drug: MEK162<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response (OR) | Objective response as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.0, was defined as participants with a best overall response of complete response (CR) or partial response (PR), were recorded from date of randomization or date of start of treatment until date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target and non-target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. | From date of randomization or date of start of treatment until date of first documentation of PD or death due to any cause, whichever occurred first (maximum duration of up to 33 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS as assessed by investigator per RECIST v1.0, was defined as time (in months) from date of randomization or date of start of treatment to first documentation of PD or date of death due to any cause or data censoring date, whichever occurred first. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of greater than or equal to (>=) 5 mm, or appearance of >=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. If a participant did not had an event, data censoring was done at the date of last adequate tumor assessment. Analysis was performed using Kaplan-Meier method. | From date of randomization or date of start of treatment until date of first documentation of PD or date of death due to any cause or date of data censoring, whichever occurred first (maximum duration of up to 33 months) | 
| Overall Survival (OS) | Overall survival was defined as the time (in months) from the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. | From date of randomization or date of start of treatment to date of death due to any cause or date of censoring, whichever occurred first (maximum duration of up to 33 months) | 
| Duration of Response (DOR) | DOR:time from first documentation of OR(confirmed CR or PR) to first documentation of PD/death due to any cause/data censoring date,whichever occurred first. As per RECIST v1.0, CR:disappearance of all target(T) and non-target(Non-T) lesions sustained for =>4 weeks. Any pathological lymph nodes(T or non-T) reduced in short axis to <10mm. PR:>=30% decrease in sum of diameters(SOD) of T lesions, taking as reference baseline SOD. PD for T lesions:at least a 20% increase in sum of diameters of T lesions, taking as reference smallest sum on study treatment, with absolute increase of >=5 mm, or appearance of >=1 new lesions.PD for Non-T lesions:unequivocal progression of pre-existing lesions/increase in overall tumor burden leading to discontinuation of therapy/appearance of new unequivocal malignant lesion.Data was censored on date of last adequate tumor assessment for participants without an event,who started new anti-cancer treatment prior to assessment,who missed >=2 tumor assessments. | From first documentation of CR or PR until first documentation of tumor progression or death due to any cause or data censoring date, whichever occurred first (maximum duration of up to 33 months) | 
| Time to Response (TTR) | TTR as assessed by investigator according to RECIST v1.0, was defined as the time (in months) from date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. | From the date of randomization or date of start of treatment to the first documentation of objective response (CR or PR) or data censoring date, whichever occurred first (maximum duration of up to 33 months) | 
| Number of Participants With Grade 3 or 4 Treatment-Emergent Adverse Reactions Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.0 | An adverse drug reaction (ADR) was any untoward medical occurrence attributed to study drug in participants who received study drug. As per NCI-CTCAE v4.0, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4:life-threatening consequence, urgent intervention indicated; Grade 5:death related to study drug. Treatment-emergent ADRs are between first dose of study drug and up to 30 days after last dose of study drug, that were absent before treatment or that worsened relative to pretreatment state. Number of participants with any Grade 3 or 4 treatment-emergent ADR were reported in this outcome measure. | Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months) | 
| Number of Participants With Serious Adverse Reactions | A serious ADR was an ADR resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening experience (immediate risk of dying); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly, important medical event. | Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months) | 
| Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Hematology) | Hematology per NCI-CTCAE included, Lymphocyte count decreased-(G1:<0.8, G2:<0.8-0.5, G3:<0.5-0.2, G4:<0.2[*10^9/L]); Lymphocyte count increased-(G2:>4-20, G3:>20[*10^9/L]); Neutrophil count decreased-(G1:<1.5, G2:<1.5-1.0, G3:<1.0-0.5, G4:<0.5[*10^9/L]); Activated partial thromboplastin time prolonged (seconds)-(G1:>1.5*upper limit normal (ULN), G2:>1.5-2.5*ULN, G3:>2.5*ULN); Platelet count decreased-(G1:<75.0, G2:<75.0-50.0, G3:<50.0-25.0, G4:<25.0[*10^9/L]); Fibrinogen decreased-(G1:<1.0-0.75*lower limit normal (LLN), G2:<0.75-0.5*LLN, G3:<0.5-0.25*LLN G4:<0.25*LLN); Anemia-(G1:<LLN-100, G2:<100-80, G3:<80 [g/L], G4:Life-threatening, G5:death); Hemoglobin increased-(G1:>0-2 g/dL above ULN, G2:>2-4 g/dL above ULN, G3:>4 g/dL above ULN); Prothrombin time (INR) increased-(G1:>1-1.5, G2:>1.5-2.5, G3:>2.5[*ULN]); WBC decreased-(G1:<3.0*10^9/L, G2:<3.0-2.0*10^9/L, G3:<2.0-1.0*10^9/L, G4:<1.0*10^9/L); WBC increased-(G3:>100,000/mm3, G4:Clinical manifestations of increase in WBC, G5:death). | Baseline up to 30 days after last dose of study drug (up to maximum of 33 months) | 
| Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Chemistries) | Albumin(G1:<30,G2:<30-20,G3:<20[g/L], G4:life-threatening, G5:death);Alkaline phosphatase(G1:>2.5,G2:>2.5-5.0,G3:>5.0-20.0, G4:>20.0[*ULN]);Creatine kinase(G1:>2.5,G2:>2.5-5,G3:>5-10,G4:>10[*ULN]);Creatinine(CT) clearance(G1:<LLN-60,G2:59-30,G3:29-15,G3:<15[ml/min/1.73m^2], G5:death);CT (G1:>1.5,G2:>1.5-3.0,G3:>3.0-6.0,G4:>6.0[*ULN]);Hypomagnesemia(G1:<0.5,G2:<0.5-0.4,G3:<0.4-0.3,G4:<0.3[mmol/L],G5:death);Hypermagnesemia(G1:>1.23,G3:>1.23-3.30, G4:>3.30[mmol/L],G5:death);Hypophosphatemia(G1:<0.8,G2:<0.8-0.6,G3:<0.6-0.3,G4:<0.3[mmol/L], G5:death);Hypokalemia(G1:<3.0,G2:<3.0,G3:<3.0-2.5,G4:<2.5[mmol/L],G5:death);Hyperkalemia(G1:>5.5,G2:>5.5-6.0,G3:>6.0-7.0, G4:>7.0[mmol/L],G5:death);AST(G1:>3.0,G2:>3.0-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]); ALT(G1:>3.0,G2:>3.0-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]);Hyponatremia(G1:<130,G3:<130-120,G4:<120[mmol/L],G5:death);Hypernatremia(G1:150,G2:>150-155,G3:>155-160,G4:>160[mmol/L],G5:death);High blood bilirubin (G1:>1.5,G2:>1.5-3.0,G3:>3.0-10.0,G4:>10.0[*ULN]). | Baseline up to 30 days after last dose of study drug (up to maximum of 33 months) | 
| Number of Participants With Shift From Baseline in Vital Signs Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Blood Pressure) | Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP). | Baseline up to 30 days after last dose of study drug (up to maximum of 33 months) | 
| Number of Participants With Markedly Abnormal Vital Sign Values: Sitting Pulse Rate | Pre-defined criteria of markedly abnormal vital signs abnormalities was defined as increase or decrease from baseline (>=15 beats per minute) in pulse rate of >=120 beats per minute or less than or equal to (<=) 50 beats per minute. | Baseline up to 30 days after last dose of study drug (up to maximum of 33 months) | 
| Number of Participants With Markedly Abnormal Vital Sign Values: Weight | Vital signs included assessment of body weight. Body weight (in kilograms) measurements included high and low. Pre-defined criteria of markedly abnormal vital signs abnormalities was defined as increase or decrease from baseline in weight of >=10%. | Baseline up to 30 days after last dose of study drug (up to maximum of 33 months) | 
| Number of Participants With Notable Electrocardiogram (ECG) Values | ECG findings included maximum value of >450 millisecond (msec), >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval corrected using Fridericia's formula (QTcF); maximum value of >450 msec, >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval corrected using Bazett's formula (QTcB); maximum value of >450 msec, >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval; RR decrease >25% and to a VR >100, RR increase >25% and to a VR <50 beats per minute for VR interval; an increase >25% and to a value >200 msec for PR interval; an increase >25% and to a value >110 msec for QRS interval. | Baseline up to 30 days after last dose of study drug (up to maximum of 33 months) | 
| Number of Participants With Change From Baseline in Abnormal Ophthalmoscopy Values- by Fundoscopy | Fundoscopy examination included an examination of the retina, vitreous, macula, optic nerve, optic nerve pallor, choroid and other new abnormalities in either or both eyes. New abnormalities were identified where the baseline assessment showed no abnormalities in a particular eye, but at the post-dose time point an abnormality was observed. New abnormalities at any time point were reported and included unscheduled assessments. | Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months) | 
| Number of Participants With Change From Baseline in Abnormal Ophthalmoscopy Values- by Slit Lamp Examination | Slit lamp examination included an examination of the conjunctiva, cornea, iris, lens, anterior chamber, lids and other new abnormalities in either or both eyes. New abnormalities were identified where the baseline assessment showed no abnormalities in a particular eye, but at the post-dose time point an abnormality was observed. New abnormalities at any time point were reported and included unscheduled assessments. | Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months) | 
| Area Under the Curve From Time Zero to End of Dosing Interval at Steady-State (AUCtau) of Binimetinib |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Maximum Plasma Concentration (Cmax) of Binimetinib |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Trough Plasma Concentration (Ctrough) of Binimetinib | Ctrough refers to plasma concentration of Binimetinib observed just before treatment administration. | Pre-dose (0 hour) on Day 15 of Cycle 1 | 
| Apparent Total Body Clearance (CL/F) of Binimetinib | Drug clearance was defined as a quantitative measure of the rate at which a drug substance was removed from the plasma. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Area Under the Curve From Time Zero to End of Dosing Interval at Steady-State (AUCtau) of Binimetinib's Metabolite |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Maximum Plasma Concentration (Cmax) of Binimetinib's Metabolite |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib's Metabolite |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib's Metabolite |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib's Metabolite |  | Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1 | 
| Trough Plasma Concentration (Ctrough) of Binimetinib's Metabolite | Ctrough refers to plasma concentration of Binimetinib's metabolite observed just before treatment administration. | Pre-dose (0 hour) on Day 15 of Cycle 1 | 
| Percent Change From Baseline in Histological Score (H-score) for Phosphorylated Extracellular Signal-Regulated Kinase (pERK) From Tumor Samples of Cytoplasmic and Nuclear Cellular Compartment | Percent change from baseline in H-score for pERK from tumor samples was assessed and summarized. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors. | Baseline up to maximum duration of up to 33 months | 
| Percent Change From Baseline in Delta CT Values for Dual Specificity Phosphatase 6 (DUSP6) Expression From Tumor Samples | The percentage change in DUSP6 gene expression was derived from the Relative Expression Ratio (RER) computed via the Delta Ct method. DUSP6, a protein coding gene was used as a biomarker of inhibition of the mitogen-activated protein kinase (MEK) pathway. | Baseline up to maximum duration of up to 33 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic melanoma,, BRAF-mutant,, NRAS-mutant