Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.
关键词
抽象
描述
There is a need for more effective therapies for patients with advanced NSCLC driven by the RAS/MEK/ERK pathway. These tumors are generally aggressive, are almost exclusively of non-squamous histology, and represent the largest group of patients with advanced NSCLC harboring specific driver mutations in Western populations.
Based on recent preclinical and clinical evidence, mitogen-activated protein kinase kinase (MEK)-inhibition plus first-line chemotherapy is a promising new treatment for patients with NSCLC and KRAS [v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog] mutations.
Binimetinib is a medication without marketing authorization. Pemetrexed and cisplatin have marketing authorization in Switzerland and in EU for the treatment of non-small cell lung cancer (NSCLC) and will be administered as standard backbone treatment according to their Swissmedic-approved indication, dose and route of administration. Binimetinib, pemetrexed and cisplatin are IMP in the context of this phase I trial.
日期
最后验证: | 01/31/2020 |
首次提交: | 11/13/2016 |
提交的预估入学人数: | 11/13/2016 |
首次发布: | 11/15/2016 |
上次提交的更新: | 02/03/2020 |
最近更新发布: | 02/04/2020 |
实际学习开始日期: | 04/11/2017 |
预计主要完成日期: | 08/31/2020 |
预计完成日期: | 08/31/2020 |
状况或疾病
干预/治疗
Drug: Combination of binimetinib, pemetrexed and cisplatin
Drug: Combination of binimetinib, pemetrexed and cisplatin
Drug: Combination of binimetinib, pemetrexed and cisplatin
相
手臂组
臂 | 干预/治疗 |
---|---|
Experimental: Combination of binimetinib, pemetrexed and cisplatin The trial consists of two parts:
Part 1: dose escalation based on the 3+3 design with 2 doses of binimetinib
Part 2: expansion cohort at the recommended maximum tolerated dose (MTD) level of binimetinib | Drug: Combination of binimetinib, pemetrexed and cisplatin Binimetinib will be administered in combination with pemetrexed and cisplatin (induction therapy), and with pemetrexed only (maintenance therapy), during the first 2 weeks of each cycle. Cycles will be repeated every 21 days. |
资格标准
有资格学习的年龄 | 18 Years 至 18 Years |
有资格学习的性别 | All |
接受健康志愿者 | 是 |
标准 | Inclusion Criteria: - Written informed consent according to the Swiss HRA and ICH-GCP regulation before registration and prior to any trial-specific procedure. - Histologically or cytologically confirmed diagnosis of NSCLC, predominantly non-squamous subtype (adenocarcinoma, large cell carcinoma, NOS). - Locally advanced or metastatic stage III-IV disease according to the 7th TNM classification, ineligible for curative treatment. - Presence of KRAS exon 2 or 3 (codon 12, 13 or 61) mutations by local testing (concomitant EGFR and ALK mutations are excluded). - CT scan showing measurable disease, which is defined as at least one lesion that can be measured in at least one dimension (non-nodal lesions ≥10 mm in longest diameter, lymph nodes ≥15 mm in short axis) according to RECIST 1.1. - Eligible for cisplatin-based chemotherapy and able to take oral medications. - WHO performance status 0-1. - Age from 18 to 75 years. - Adequate hematological values: hemoglobin ≥ 90 g/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L. - Adequate hepatic function: total bilirubin ≤ 1.5 x ULN and < 34.2 μmol/L; ALT and alkaline phosphatase ≤ 2.5 x ULN. - Adequate renal function: calculated creatinine clearance ≥ 60 mL/min, according to the formula of Cockcroft-Gault. - Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% as determined by echocardiogram; QTcF interval must be ≤ 480 ms. - Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and 6 months thereafter. A negative serum pregnancy test before inclusion into the trial is required for all women with child-bearing potential. - Men agree not to father a child during trial treatment and 6 months thereafter. Exclusion Criteria: - NSCLC with any additional small cell carcinoma (SCLC) component by local diagnostic pathology report. - Meningeosis carcinomatosa, symptomatic or untreated central nervous system (CNS) metastases. Patients with treated, controlled CNS metastases can be enrolled 2 weeks after the end of radiotherapy if asymptomatic (no residual neurologic deficits) and no longer on corticosteroids. - Previous or concurrent malignancy with the following exceptions: - adequately treated basal cell or squamous cell carcinoma of the skin (adequate wound healing is required prior registration), - in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 5 years prior registration, - superficial bladder cancer, prostate intraepithelial neoplasm, other noninvasive or indolent malignancy, or other solid tumor treated curatively and without evidence of recurrence for at least 5 years prior registration. - Leptomeningeal disease. - Concurrent radiotherapy (patients with prior radiotherapy other than for brain metastases ≥ 7 days prior to registration can be enrolled). - Previous systemic therapy for advanced NSCLC; previous adjuvant or neoadjuvant chemotherapy allowed if last dose was administered at least 6 months ago. - Major surgery within 3 weeks before registration. - Concurrent treatment with any other experimental drug or other anticancer therapy. - Impaired cardiovascular function or clinically severe or uncontrolled cardiovascular diseases, including any of the following: - congestive heart failure NYHA III or IV, - history of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6 months prior to registration, - symptomatic chronic heart failure (G2 or higher), history or current evidence of clinically significant cardiac arrhythmia requiring medication and/or conduction abnormality < 6 months prior to registration except atrial fibrillation and paroxysmal supraventricular tachycardia. - Uncontrolled arterial hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite medical treatment. - History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyper-viscosity or hypercoagulability syndromes); history of retinal degenerative disease. - History of Gilbert's syndrome. - Neuromuscular disorders that are associated with elevated creatine phosphokinase (CPK; e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). - Neuropathy (> G1) or hearing impairment/ tinnitus (> G1). - Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection). - History of thromboembolic or cerebrovascular events within 6 months prior to registration, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli. - Known history of acute or chronic pancreatitis. - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) within 12 months prior to registration. - Known positive serology for HIV (human immunodeficiency virus), active hepatitis B, and/or active hepatitis C infection. - Active infection within 14 days prior to registration. - Planning on embarking on a new strenuous exercise regimen after first dose of binimetinib (NB: muscular activities, such as strenuous exercise, that can result in significant increases in plasma CPK levels should be avoided while on binimetinib treatment). - Known lactose intolerance. - Known hypersensitivity to the trial drugs or hypersensitivity to any other component of the trial treatment, including premedication. - Any concomitant drugs contraindicated for use with pemetrexed and cisplatin according to the Swissmedic-approved current product information or with binimetinib according to the latest version of the Investigator's Brochure. - Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications. |
结果
主要结果指标
1. Dose-limiting toxicities (DLTs) [within 21 days from the first dose]
次要成果指标
1. Objective response (OR) [at 30 months after start of trial]
2. Progression-free survival (PFS) [at 30 months after start of trial]
3. Overall survival (OS) [at 30 months after start of trial]
4. Adverse events (AEs) [at 30 months after start of trial]