A Phase I, Multicenter, Open-label, Dose-escalation Study of Oral LGX818 in Adult Patients With Locally Advanced or Metastatic BRAF Mutant Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 107
- 试验地点
- 20
- 主要终点
- Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase
研究概览
简要总结
CLGX818X2101 is a first-time in-human, phase I study to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of daily administered LGX818 (daily, twice daily and/or every-other-day), a RAF kinase inhibitor. Patients with locally advanced or metastatic melanoma harboring the BRAF V600 mutation (during dose escalation phase and expansion phase) and patients with metastatic colorectal cancer harboring the BRAF V600 mutation (during the expansion phase) will be enrolled. The study consists of a dose escalation part were cohorts of patients will receive escalating oral doses of LGX818, followed by a safety dose expansion part were patients will be treated with oral dose of LGX818 given at the MTD or RP2D.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •For the dose escalation phase:
- •Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]). For the dose expansion phase: (i) Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or (ii) confirmed diagnosis and non-resectable advanced metastatic colorectal cancer (mCRC) for which no further effective standard therapy exists.
- •Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation.
- •Evidence of measurable disease
排除标准
- •Previous therapy with a MEK inhibitor.
- •Symptomatic or untreated leptomeningeal disease.
- •Symptomatic or untreated brain metastasis.Patients previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with verification by imaging.
- •Known acute or chronic pancreatitis.
- •Clinically significant cardiac disease
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818
- •Previous or concurrent malignancy. Exceptions to this exclusion criteria include: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry.
- •Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
- •History of thromboembolic or cerebrovascular events within the last 6 months
- •Other protocol-defined inclusion/exclusion criteria may apply
研究组 & 干预措施
LGX818 - Dose escalation
干预措施: LGX818 (Drug)
LGX818 - Dose Expansion at MTD or RP2D
干预措施: LGX818 (Drug)
结局指标
主要结局
Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase
时间窗: Up to 28 days
DLT= Adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within first 28 days of treatment with encorafenib and met any of following criteria: \>=grade (G)3 neutropenia or thrombocytopenia for \>7 days; G4 thrombocytopenia; febrile neutropenia; \>=G3 serum creatinine, blood bilirubin; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and lipase and/or serum amylase (\>=G3 for \> 7 consecutive days or G4); \>=G3 ALT or AST and \>=G2 blood bilirubin; \>=G3 persistent hypertension with more than one drug or more intensive therapy or cardiac disorders or AE excluding on-target side-effect that is manageable; G3 fatigue/asthenia for \>7 consecutive days; \>= G3 vomiting or nausea or diarrhea lasting more than 48 hours despite treatment; \>=G3 pancreatitis, rash/photosensitivity (G3 for \> 7 consecutive days despite skin toxicity treatment or G4); G3 or G4 eye disorders.
Number of Participants With DLT During Dose Expansion Phase
时间窗: Up to 28 days
DLT= Adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within first 28 days of treatment with encorafenib and met any of following criteria: \>=grade (G)3 neutropenia or thrombocytopenia for \>7 days; G4 thrombocytopenia; febrile neutropenia; \>=G3 serum creatinine, blood bilirubin; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and lipase and/or serum amylase (\>=G3 for \> 7 consecutive days or G4); \>=G3 ALT or AST and \>=G2 blood bilirubin; \>=G3 persistent hypertension with more than one drug or more intensive therapy or cardiac disorders or AE excluding on-target side-effect that is manageable; G3 fatigue/asthenia for \>7 consecutive days; \>= G3 vomiting or nausea or diarrhea lasting more than 48 hours despite treatment; \>=G3 pancreatitis, rash/photosensitivity (G3 for \> 7 consecutive days despite skin toxicity treatment or G4); G3 or G4 eye disorders.
次要结局
- Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase(From start of study treatment until 30 days after last dose of study treatment (maximum of 556.1 weeks of treatment exposure))
- Number of Participants With AEs and SAEs During Dose Expansion Phase(From start of study treatment until 30 days after last dose of study treatment (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively))
- Progression Free Survival (PFS): Dose Escalation Phase(From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 556.1 weeks of treatment exposure))
- PFS: Dose Expansion Phase(From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively))
- Duration of Response (DOR): Dose Escalation Phase(From first observation of response until first time of PD or death due to any cause (Maximum of 556.1 weeks of treatment exposure))
- Time to Response (TTR): Dose Escalation Phase(From date of start of treatment until CR or PR or censoring date (maximum of 556.1 weeks of treatment exposure))
- DOR: Dose Expansion Phase(From first observation of response until first time of PD or death due to any cause (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively))
- TTR: Dose Expansion Phase(From date of start of treatment until CR or PR or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively))
- Overall Survival (OS): Dose Expansion Phase(From start of study treatment until date of death or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively))
- Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase(Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days))
- Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase(Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days))
- Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase(Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days))
- Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase(Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days))
- Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase(Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days))
- Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase(Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days))
- Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase(Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days))
- Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation(From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 556.1 weeks of treatment exposure))
- Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase(Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days))
- Vz/F of LGX818: Dose Expansion Phase(Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days))
- Tmax of LGX818: Dose Expansion Phase(Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days))
- AUCinf of LGX818: Dose Expansion Phase(Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days))
- AUCtau of LGX818: Dose Expansion Phase(Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days))
- t1/2 of LGX818: Dose Expansion Phase(Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days))
- CL/F of LGX818: Dose Expansion Phase(Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days))
- Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion((Baseline) last non-missing value prior to the first dose (Baseline))
- Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion(From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively))