Description:
Two-arm, randomized, prospective, open-label, multi-center, phase III study to compare the
efficacy and safety of MEK162 (45 mg BID) versus dacarbazine (1000 mg/m2 IV every 3 weeks) in
patients with advanced (Stage IIIC) unresectable or metastatic (Stage IV) NRAS Q61
mutation-positive cutaneous or unknown primary melanoma. The mutation analysis will be
performed at a central laboratory. Only those patients with Q61 mutation per central
laboratory and meet all eligibility criteria will be randomized. A total of 393 patients will
be randomized 2:1 to receive either MEK162 or dacarbazine. Patients will be stratified
according to AJCC stage (IIIC, IVM1a, and IVM1b versus IVM1c), ECOG Performance status (0
versus 1) and any prior number of lines of immunotherapy (immunotherapies versus none). This
study will use an Interactive Response Technology (IRT). The primary end point of the study
is progression-free survival. Key secondary end point is overall survival
Title
- Brief Title: Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma
- Official Title: The NEMO Trial (NRAS Melanoma and MEK Inhibitor):A Randomized Phase III, Open Label, Multicenter, Two-arm Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Patients With Advanced Unresectable or Metastatic NRAS Mutation-positive Melanoma
Clinical Trial IDs
- ORG STUDY ID:
CMEK162A2301
- SECONDARY ID:
C4211002
- SECONDARY ID:
2012-003593-51
- NCT ID:
NCT01763164
Conditions
- Metastatic or Unresectable Cutaneous Melanoma
Interventions
| Drug | Synonyms | Arms |
|---|
| MEK162 | | MEK162 |
| Dacarbazine | | Dacarbazine |
Purpose
Two-arm, randomized, prospective, open-label, multi-center, phase III study to compare the
efficacy and safety of MEK162 (45 mg BID) versus dacarbazine (1000 mg/m2 IV every 3 weeks) in
patients with advanced (Stage IIIC) unresectable or metastatic (Stage IV) NRAS Q61
mutation-positive cutaneous or unknown primary melanoma. The mutation analysis will be
performed at a central laboratory. Only those patients with Q61 mutation per central
laboratory and meet all eligibility criteria will be randomized. A total of 393 patients will
be randomized 2:1 to receive either MEK162 or dacarbazine. Patients will be stratified
according to AJCC stage (IIIC, IVM1a, and IVM1b versus IVM1c), ECOG Performance status (0
versus 1) and any prior number of lines of immunotherapy (immunotherapies versus none). This
study will use an Interactive Response Technology (IRT). The primary end point of the study
is progression-free survival. Key secondary end point is overall survival
Trial Arms
| Name | Type | Description | Interventions |
|---|
| MEK162 | Experimental | | |
| Dacarbazine | Active Comparator | | |
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of locally advanced, unresectable or metastatic cutaneous or melanoma of
unknown primary AJCC Stage IIIC or IV (uveal and mucosal melanoma are excluded)
- Presence of NRAS Q61 mutation in tumor tissue prior to randomization as determined by
a Novartis designated central laboratory
- Naïve untreated patients or patients who have progressed on or after any number of
prior lines of immunotherapy for unresectable locally advanced or metastatic melanoma
- Evidence of at least one measurable lesion as detected by radiological or photographic
methods
- Adequate bone marrow, organ function, cardiac and laboratory parameters
- Normal functioning of daily living activities
Exclusion Criteria:
- Any untreated CNS metastases
- Uveal or mucosal melanoma
- History of or current evidence of retinal vein occlusion (RVO) or risk factors of RVO
- Patients with washout period < 6 weeks from the last dose of ipilimumab or other
immunotherapy.
- Previous systemic chemotherapy for unresectable locally advanced or metastatic
melanoma.
- History of Gilbert's syndrome
- Prior therapy with a MEK- inhibitor
- Impaired cardiovascular function or clinically significant cardiovascular diseases
- Uncontrolled arterial hypertension despite medical treatment
- HIV positive or active Hepatitis A or B
- Impairment of gastrointestinal function
- Patients who have undergone major surgery or radiotherapy ≤ 3 weeks prior to starting
study drug or who have not recovered from side effects of such procedure;
- Patients with neuromuscular disorders that are associated with elevated CK.
- Pregnant or nursing (lactating) women
- Medical, psychiatric, cognitive or other conditions that may compromise the patient's
ability to understand the patient information, give informed consent, comply with the
study protocol or complete the study
Other protocol-defined inclusion/exclusion criteria may apply
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 |
| Time Frame: | From the date of randomization to the date of the first documented PD or death, whichever occurred first (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm) |
| Safety Issue: | |
| Description: | PFS: time from randomization to first documented PD or death due to any cause, whichever occurred first. RECIST 1.1, PD: >=20% increase in sum of diameter of target lesions (TLs) taking as reference the smallest sum on study (including baseline sum), sum must also be an absolute increase of >=5 mm; unequivocal progression of existing non-TLs; appearance of >=1 lesion. Complete response (CR): disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs. Partial response (PR): >=30% decrease in sum of diameter of all TLs, referring baseline sum of diameters. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor increase in lesions qualified for PD referring smallest sum diameter. With no event at time of analysis cut-off or at start of any new anti-neoplastic therapy, PFS censored at date of last adequate tumor assessment of CR, PR or SD. |
Secondary Outcome Measures
| Measure: | Overall Survival (OS) |
| Time Frame: | From the date of randomization to the date of death (maximum up to 107 weeks for binimetinib arm; maximum up to 88 weeks for dacarbazine arm) |
| Safety Issue: | |
| Description: | Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a participant was not known to have died, overall survival was censored at the date of last known date participant alive. |
| Measure: | Overall Response Rate (ORR) |
| Time Frame: | From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm) |
| Safety Issue: | |
| Description: | ORR: percentage of participants with best overall response (BOR) of CR or PR. BOR: best response recorded from start of treatment until CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. ORR is reported for confirmed and unconfirmed responses. Confirmed CR or PR = at least 2 determinations of CR or PR at least 4 weeks apart before PD. PD: >=20% increase in sum of diameter of all measured target lesions, taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non TLs. Appearance of at least 1 new lesion. |
| Measure: | Time to Response (TTR) |
| Time Frame: | From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm) |
| Safety Issue: | |
| Description: | TTR: time between date of randomization until first documented response of CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: >=20% increase in sum of diameter of all measured TLs taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-TLs. Appearance of >=1 new lesion. Participants who did not achieve PR or CR censored at last adequate tumor assessment date when they did not have PFS event (time from date of randomization to date of first documented PD or death due to any cause, whichever occur first) or at maximum follow-up when they had PFS event. |
| Measure: | Duration of Objective Response (DOR) |
| Time Frame: | From the date of first documented response (CR or PR) to the first documented progression or death (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm) |
| Safety Issue: | |
| Description: | DOR: time from date of first documented response (CR or PR) to first documented progression or death due to underlying cancer. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: >=20% increase in sum of diameter of all measured target lesions taking as reference smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion. If a participant with a CR or PR had no PD or death due to underlying cancer, participants was censored at date of last adequate tumor assessment. |
| Measure: | Disease Control Rate (DCR) |
| Time Frame: | From date of randomization until first documented response of CR, PR, SD or non-CR/non-PD (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm) |
| Safety Issue: | |
| Description: | DCR was calculated as the percentage of participants with a BOR of CR, PR, SD RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to <10 mm; normalization of tumor marker level for non-TLs; b) PR: >=30% decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; c) SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD taking as reference the smallest sum diameters; d) PD: >=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion. |
| Measure: | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |
| Time Frame: | From baseline up to 219.4 weeks for binimetinib arm; From baseline up to 123.9 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE was defined as one of the following: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE was defined as an AE with onset date occurring during the on-treatment period. AEs included all SAEs and non-SAEs. |
| Measure: | Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 |
| Time Frame: | From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | Clinically notable shifts are defined as worsening by at least 2 grades or to >= grade 3. Severity was graded as 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 AE. |
| Measure: | Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 |
| Time Frame: | From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | Clinically notable shifts are defined as worsening by at least 2 grades or to >= grade 3. Severity was graded as 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 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 AE. |
| Measure: | Number of Participants With Clinically Notable Vital Signs |
| Time Frame: | From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | Abnormalities criteria included: low/high pulse rate (beats per minute [bpm]):<=50bpm with decrease from baseline >=15bpm/>=120bpm with increase from baseline >=15bpm; Low/high systolic blood pressure (millimeters of mercury [mmHg]): <=90mmHg with decrease from baseline >=20mmHg/>=160mmHg with increase from baseline >=20mmHg; Low/high diastolic blood pressure [mmHg]: <=50mmHg with decrease from baseline >=15mmHg/>=100mmHg with increase from baseline >=15mmHg; Low/high body weight (kilogram [kg]): >=20% decrease from baseline / >=10% increase from baseline; Low/high body temperature (degree Celsius [°C]): <=36°C / >= 37.5°C |
| Measure: | Number of Participants With Notable Electrocardiogram (ECG) Values |
| Time Frame: | From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | Criteria for notable ECG values were as follow: QT interval (in millisecond [msec]) new (newly occurring post-baseline value) greater than (>) 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Fredericia formula (QTcF) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Bazett's formula (QTcB) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; heart rate in bpm new (newly occurring post-baseline value) <60 and >100. |
| Measure: | Number of Participants With Adverse Events of Special Interest: Cardiac Events |
| Time Frame: | From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. 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 AE. Here, in this outcome measure data is reported for events falling in any of the grades. |
| Measure: | Number of Participants With Clinically Significant Findings in Physical Examination |
| Time Frame: | From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | A complete physical examination included the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological systems. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic examinations were performed. Clinical significance in physical examination was reported as adverse events. |
| Measure: | Number of Participants With Adverse Events of Special Interest: Ocular Events |
| Time Frame: | From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. 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 ADL; Grade 3: Severe or medically significant but not immediately sight threatening; Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the affected eye. Here, in this outcome measure data is reported for events falling in any of the grades. |
| Measure: | Plasma Concentration of Binimetinib |
| Time Frame: | Day 1 of Week 1: Pre-dose, 1, 1.5, 2, 10 hours post-dose; Day 1 of Weeks 4, 7: Pre-dose, 1.5 hours post-dose; Day 1 of Weeks 10, 13: Pre-dose |
| Safety Issue: | |
| Description: | |
| Measure: | Time to Definitive 10% Deterioration in Global Health Status Score of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) |
| Time Frame: | From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm |
| Safety Issue: | |
| Description: | The time to definitive 10% deterioration was defined as the time from the date of randomization to the date of event, which was defined as death due to any cause or at least 10% worsening of the corresponding scale score, relative to baseline, with no later improvement above this threshold observed during the course of the study or death due to any cause. If a participant had no event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last adequate health related quality of life (HRQoL) evaluation. EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life. |
| Measure: | Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 |
| Time Frame: | Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57 |
| Safety Issue: | |
| Description: | EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a h global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy. |
| Measure: | Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 |
| Time Frame: | Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57 |
| Safety Issue: | |
| Description: | EQ-5D-5L, is a standardized measure of health utility that provides a single index value for one's health status. EQ-5D-5L contained 1 item for each of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Index score: participant responses to the 5 dimensions reflected a specific health state that corresponded to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health). Higher index scores = better health state. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy. |
| Measure: | Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) |
| Time Frame: | From baseline up to 73 weeks 3 days for binimetinib arm; From baseline up to 57 weeks 3 days for dacarbazine arm |
| Safety Issue: | |
| Description: | ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair and 5= dead. Definitive deterioration is defined as on treatment death due to any cause or decrease in ECOG PS by at least one category from baseline score. |
| Measure: | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) |
| Time Frame: | For both arms: Baseline, Weeks 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55 and 30-day Follow-up For binimetinib only: Weeks 58, 61, 64, 67, 70, 73 |
| Safety Issue: | |
| Description: | ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair confined to bed or chair more than 50% of waking hours and 5= dead. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy. |
| Measure: | Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline |
| Time Frame: | Baseline |
| Safety Issue: | |
| Description: | Number of participants with NRAS mutation status at baseline were reported. |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Pfizer |
Trial Keywords
- Melanoma
- Cutaneous melanoma
- Skin disease
- Skin cancer
- Skin Neoplasms
- Neoplasm Metastasis
Last Updated
March 22, 2021
