Phase II, Multi-center, Open-label Study of Single-agent LGX818 Followed by a Rational Combination With Agents After Progression on LGX818, in Adult Patients With Locally Advanced or Metastatic BRAF V600 Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 15
- 试验地点
- 2
- 主要终点
- Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II)
研究概览
简要总结
The primary purpose of the Phase II CLGX818X2102 study is to assess the anti-tumor activity of LGX818 in combination with selected agents.
详细描述
This is a phase II two part multi-center, open-label study. Part I: LGX818 single agent treatment until progression Part II: Combination treatments of LGX818 + MEK162, or BKM120, or BGJ398, or INC280, or LEE01 to assess the clinical efficacy, to further evaluate the safety of the drug combinations in patients with locally advanced or metastatic BRAF mutant melanoma after relapse on LGX818, and to determine the maximum tolerated dose of the combinations (when not established previously). These drug combinations are selected and assigned to patients based on documentation of molecular resistance mechanism.
Patients with BRAF mutant melanoma treated by LGX818 single agent in other studies can be enrolled directly in Part II of CLGX818X2102 after relapse.
Dose-escalations in the combination arms for which no MTD has been established will be based on the recommendations of a Bayesian logistic regression model guided by an escalation with overdose control criterion.
After careful evaluation of slow enrollment and the BRAF-mutant melanoma treatment landscape, recruitment was permanently halted on 26-Jul-2014.
This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •locally advanced or metastatic melanoma
- •confirmed BRAF V600 mutation
- •patients naïve to a selective BRAF inhibitor
- •fresh tumor biopsy at baseline, and patient agrees for a mandatory biopsy at the time of relapse
- •life expectancy ≥ 3 months
- •World Health Organization (WHO) Performance Status ≤ 2.
排除标准
- •Previous treatment with RAF-inhibitor
- •Symptomatic or untreated leptomeningeal disease
- •Symptomatic brain metastases.
- •Known acute or chronic pancreatitis
- •Clinically significant cardiac disease
- •AST/SGOT and ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral interventional drug
- •Previous or concurrent malignancy.
- •Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation
- •Specific exclusion criteria for each treatment arm:
- •LGX818/MEK162:
- •History or current evidence of retinal disease History of Gilbert's syndrome.
- •LGX818/BKM120:
- •Patients with diabetes mellitus requiring insulin treatment Patient has mood disorders
- •LGX818/BGJ398:
- •History and/or current evidence of ectopic mineralization/ calcification Current evidence of corneal disorder/ keratopathy Patients with current evidence of endocrine alteration of calcium/phosphate homeostasis.
- •History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade ≥ 3 and/or magnesium levels below the clinically relevant lower limits before study entry.
- •Ionized (i) calcium (Ca) > ULN Serum inorganic phosphorus (Pi) > ULN
- •LGX818/LEE011 History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade ≥ 3 and/or magnesium levels below the clinically relevant lower limits before study entry.
研究组 & 干预措施
LGX818 single agent
Patients had to have written documentation of a BRAFV600 mutation, which was to have been obtained locally on a fresh tumor biopsy (preferred) or on the most recent archival tumor sample available.
干预措施: LGX818 (Drug)
结局指标
主要结局
Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II)
时间窗: Baseline through study completion (approximately 2 years)
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: * Complete Response (CR) is the Disappearance of all target lesions. * Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. * Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. * Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
次要结局
- Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways(Baseline and at progression with LGX818 single agent treatment)
- Incidence of Dose Limiting Toxicities (DLTs) (Part II)(Baseline through study completion (approximately 2 years))
- Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I)(Baseline through completion of Part I of the study (approximately 2 years))
- Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II)(Entry to Part II of the study through study completion (approximately 22 days))
- Plasma Concentration and Derived Pharmacokinetic Parameters(Baseline through study completion (approximately 2 years))