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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 402
- 试验地点
- 191
- 主要终点
- Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
研究概览
简要总结
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
MEK162
干预措施: MEK162 (Drug)
Dacarbazine
干预措施: Dacarbazine (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
时间窗: 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)
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.
次要结局
- Overall Survival (OS)(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))
- Duration of Objective Response (DOR)(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))
- Number of Participants With Clinically Notable Vital Signs(From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm)
- Overall Response Rate (ORR)(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))
- Disease Control Rate (DCR)(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))
- Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(From baseline up to 219.4 weeks for binimetinib arm; From baseline up to 123.9 weeks for dacarbazine arm)
- Time to Response (TTR)(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))
- Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03(From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm)
- Number of Participants With Notable Electrocardiogram (ECG) Values(From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm)
- Number of Participants With Adverse Events of Special Interest: Cardiac Events(From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm)
- Number of Participants With Clinically Significant Findings in Physical Examination(From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm)
- Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03(From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm)
- Number of Participants With Adverse Events of Special Interest: Ocular Events(From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm)
- Plasma Concentration of Binimetinib(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)
- 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)(From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm)
- 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(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)
- 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(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)
- Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)(From baseline up to 73 weeks 3 days for binimetinib arm; From baseline up to 57 weeks 3 days for dacarbazine arm)
- Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)(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)
- Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline(Baseline)