A Phase Ib/II Multi-center, Open Label, Dose Escalation Study of WNT974, LGX818 and Cetuximab in Patients With BRAFV600-mutant KRAS Wild-type Metastatic Colorectal Cancer Harboring Wnt Pathway Mutations
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 5
- 主要终点
- Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb)
研究概览
简要总结
The purpose of this study is to assess the safety and anti-tumor activity of the triple combination of WNT974, LGX818 and cetuximab in BRAFV600-mutant mCRC with RNF43 mutations or RSPO fusions.
The design of this study is based upon the translational and pre-clinical data that suggest that Wnt pathway signals, increased due to RNF43 mutations or RSPO fusions, cooperate with the EGFR and BRAF signals to maintain the growth of BRAFV600 CRCs. Inhibition of these signals with the triple combination of WNT974, LGX818 and cetuximab may result in anti-tumor activity.
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
- •Male or female aged ≥ 18 years
- •Histological or cytological confirmed metastatic colorectal cancer
- •Written documentation of KRAS wild-type status and BRAFV600-mutation with RNF43 mutation and/or RSPO fusion
- •Progression of disease after at least one prior standard of care regimen or intolerant to irinotecan based regimens
- •Availability of a representative tumor specimen (primary or metastatic, archival or newly obtained)
- •Measurable disease as per RECIST v1.1
- •Eastern cooperative oncology group (ECOG) performance status ≤ 2
排除标准
- •Phase II only: Prior treatment with RAF inhibitors, Wnt pathway inhibitors, cetuximab, panitumumab, and/or other EGFR inhibitors
- •Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed to enroll
- •Current treatment with medications or consuming foods that are strong inhibitors or inducers of CYP3A4/5 or herbal medications and that cannot be discontinued at least one week prior to the start of treatment.
- •Symptomatic or untreated leptomeningeal disease
- •Acute or chronic pancreatitis
- •Clinically significant cardiac disease
- •Patients with any of the following laboratory values at Screening/baseline
- •Absolute neutrophil count (ANC) <1,500/mm3
- •Platelets < 100,000/mm3
- •Hemoglobin < 9.0 g/dL
- •Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% lower limit of normal
- •Serum total bilirubin >1.5 x ULN
- •AST/SGOT and/or ALT/SGPT > 2.5 x ULN, (> 5 x ULN if liver metastases present)
- •Patients with impaired hepatic function as defined by Childs-Pugh class B or C
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral WNT974/LGX818
- •Other protocol-defined inclusion/exclusion criteria may apply
研究组 & 干预措施
WNT974, LGX818 and cetuximab combo
Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab
干预措施: WNT974 (Drug)
WNT974, LGX818 and cetuximab combo
Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab
干预措施: LGX818 (Drug)
WNT974, LGX818 and cetuximab combo
Phase l: Dose Escalation phase; Phase ll: SIngle group assessing the triple combination of WNT974, LGX818 and cetuximab
干预措施: Cetuximab (Biological)
结局指标
主要结局
Incidence of Dose Limiting Toxicities and exposure (AUC C1D15) to WNT974 and LGX818 (phase lb)
时间窗: 12 months
Phase Ib: To estimate the MTD(s) and/or RP2D(s) of the triple combination of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant, KRAS wild-type (WT) mCRC harboring upstream Wnt pathway mutations.
Overall response rate in phase II
时间窗: 30 months
Phase II: To estimate the preliminary anti-tumor activity of the RP2D(s) of the combination of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant metastatic CRC harboring upstream Wnt pathway mutations
次要结局
- Number of participants with Adverse Events as a measure of safety and tolerability (phase lb/ll)(30 months)
- Time to response (TTR) (phase lb/ll)(36 months)
- Number of participants with Serious Adverse Events as a measure of safety and tolerability(phase lb/ll)(30 months)
- Biomarker activations for WNT and RTK-MAPK pathways (phase Ib/II)(32 months)
- Number of participants with dose interruptions and dose reductions (phase Ib/II)(30 months)
- Overall response rate (ORR) (phase lb)(36 months)
- Overall survival (OS) (phase lb/ll)(36 months)
- Duration of response (DOR) (phase lb/ll)(36 months)
- Progression free survival (PFS) (phase lb/ll)(36 months)
- Plasma concentration of WNT974, LHA333, LGX818 (phase lb/ll)(30 months)
- Disease control rate (DCR) (phase lb/ll)(36 months)