A Phase II, Multicenter Study of Oral MET Inhibitor INC280 in Adult Patients With EGFR Wild-type (wt), Advanced Non-small Cell Lung Cancer (NSCLC) (Geometry Mono-1)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 373
- 试验地点
- 14
- 主要终点
- Overall Response Rate (ORR) by Blinded Independent Review Committee (BIRC) Assessment
研究概览
简要总结
Study to evaluate the efficacy and safety of capmatinib as a single-agent treatment for subjects with advanced/metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) who had wild-type epidermal growth factor receptor (EGFR wt) (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK)-negative rearrangement, and mesenchymal epithelial transition (MET) mutations leading to exon 14 deletion (referred to as MET mutation hereafter) and/or MET amplification.
详细描述
This was a Phase II, multicenter, open-label study. Patients were enrolled in different cohorts based on their MET status (amplification and/or mutation) and prior treatment status: Cohort 1a, Cohort 1b, Cohort 2, Cohort 3, Cohort 4, Cohort 5a, Cohort 5b, Cohort 6, and Cohort 7. MET mutation (by RT-PCR) and/or MET amplification status by gene copy number (GCN, by FISH) was determined by central laboratory.
Patients in Cohorts 1, 2, 3, and 4 had previously failed 1 or 2 prior lines of systemic therapy, while patients enrolled in Cohorts 5 and 7 were treatment-naïve for advanced disease/metastatic disease. Patients enrolled in Cohort 6 had failed 1 prior line of systemic therapy for advanced/ metastatic disease.
Patients with MET mutation were enrolled in Cohort 4 (pre-treated), Cohort 5b (treatment naïve) or Cohort 7 (treatment naïve expansion cohort of Cohort 5b), irrespective of their MET GCN. The enrollment in expansion Cohort 7 started after the completion of enrollment in Cohort 5b.
Patients without MET mutation, were enrolled in Cohorts 1a, 1b, 2, 3 (pre-treated) or 5a (treatment naïve), based on their MET GCN. Patients enrolled in Cohort 6 (expansion cohort of Cohort 1a and Cohort 4) had either MET GCN ≥10 without MET mutation (Cohort 6.1) or MET mutation, irrespective to their MET GCN (Cohort 6.2). The enrollment in Cohort 6 started upon enrollment completion of the respective Cohort 1a or Cohort 4.
All participants in the study received oral capmatinib 400 mg twice daily. A treatment cycle was defined as 21 days. Treatment with capmatinib continued until patient experienced any of the following: disease progression according to RECIST 1.1 as determined by investigator and confirmed by Blinded Independent Review Committee (BIRC), unacceptable toxicity that precluded further treatment, treatment discontinuation at the discretion of the Investigator or patient, lost to follow-up, or death. Treatment with capmatinib was allowed beyond RECIST 1.1-defined disease progression (as determined by investigator and confirmed by BIRC) if, in the judgment of the investigator, there was evidence of clinical benefit and the patient wished to continue on the study treatment. All patients continued to have safety evaluations for 30 days after the last dose of study treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Subjects with Stage IIIB or IV NSCLC (any histology) at the time of study entry
- •Subjects with histologically or cytologically confirmed diagnosis of NSCLC that is:
- •EGFR wt status (for exon 19 deletions and exon 21 L858R substitution mutations)
- •and ALK rearrangement-negative
- •and MET-mutation and/or amplification status (as defined in the protocol).
- •For Cohorts 1a, 1b, 2, 3, 4 subjects must have failed one or two prior lines of systemic therapy for advanced disease (stage IIIB or IV NSCLC). For Cohort 6, subjects must have failed one prior line of systemic therapy for advanced disease (stage IIIB or IV NSCLC).
- •For Cohorts 5a, 5b, and 7, subjects must not have received any systemic therapy for advanced disease (stage IIIB or IV NSCLC).
- •Subjects with at least one measurable lesion as defined by RECIST 1.
- •A previously irradiated site lesion may only be counted as a target lesion if there was clear sign of progression since the irradiation.
- •Subjects who recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (Common Terminology Criteria for Adverse Events [CTCAE] v 4.03). Subjects with any grade of alopecia were allowed to enter the study.
- •Subjects with adequate organ function
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
排除标准
- •Prior treatment with crizotinib, or any other MET or HGF inhibitor
- •Characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations.
- •Characterized ALK-positive rearrangement.
- •Symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
- •Clinically significant, uncontrolled heart diseases
- •Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting capmatinib or subjects who had not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to starting capmatinib or subjects who had not recovered from radiotherapy-related toxicities.
- •Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting capmatinib was allowed.
- •Receiving treatment with strong inducers of CYP3A4 and/or any enzyme-inducing anticonvulsant and could not be discontinued ≥ 1 week prior to the start of treatment with capmatinib and for the duration of the study.
- •Receiving treatment with unstable or increasing doses of corticosteroids.
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of capmatinib.
- •Applicable to Cohorts 1-4 and Cohort 6 only: previous anticancer and investigational agents within 4 weeks or ≤ 5 × half-life of the agent (whichever was longer) before first dose of- capmatinib. If previous treatment was a monoclonal antibody, then the treatment must have been discontinued ≥ 4 weeks before first dose of capmatinib. If previous treatment was an oral targeted agent, then the treatment must have been discontinued ≥ 5 × half-life of the agent before the first dose of capmatinib.
- •Pregnant or nursing (lactating) women.
- •Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 7 days after stopping treatment
- •Sexually active males unless they used a condom during intercourse while taking drug and for 7 days after stopping treatment and should not father a child in this period.
- •Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
研究组 & 干预措施
Cohort 1a: Pre-treated patients with MET GCN ≥ 10 (2/3L)
Pre-treated patients with MET GCN ≥ 10 treated with INC280 at 400mg BID as second or third line (2/3L)
干预措施: Capmatinib (Drug)
Cohort 1b:Pre-treated patients with MET GCN ≥ 6 and < 10 (2/3L)
Pre-treated patients with MET GCN ≥ 6 and < 10 treated with INC280 at 400 mg BID as second or third line (2/3L)
干预措施: Capmatinib (Drug)
Cohort 2: Pre-treated patients with MET GCN ≥ 4 and < 6 (2/3L)
Pre-treated patients with MET GCN ≥ 4 and < 6 treated with INC280 at 400mg BID as second or third line (2/3L)
干预措施: Capmatinib (Drug)
Cohort 3: Pre-treated patients with MET GCN < 4 (2/3L)
Pre-treated patients with MET GCN < 4 treated with INC280 at 400mg BID as second or third line (2/3L)
干预措施: Capmatinib (Drug)
Cohort 4: Pre-treated patients with MET mutation regardless of MET GCN (2/3L)
Pre-treated patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as second or third line (2/3L)
干预措施: Capmatinib (Drug)
Cohort 5a: Treatment-naïve patients with MET GCN ≥10 (1L)
Treatment-naïve patients with MET GCN ≥10 treated with INC280 at 400mg BID as first-line (1L)
干预措施: Capmatinib (Drug)
Cohort 5b: Treatment-naïve patients with MET mutation regardless of MET GCN (1L)
Treatment-naïve patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as first line (1L)
干预措施: Capmatinib (Drug)
Cohort 6.1 (expansion of Cohort 1a): Pre-treated patients MET GCN ≥ 10 without MET mutation (2L)
Pre-treated patients with MET GCN ≥ 10 without MET mutation treated with INC280 at 400 mg BID as second line (2L) (expansion cohort of Cohort 1a)
干预措施: Capmatinib (Drug)
Cohort 6.2 (expansion of Cohort 4): Pre-treated patients with MET mutation (2L)
Pre-treated patients with MET mutation regardless of MET GCN treated with INC280 at 400 mg BID as second line (2L)(expansion of Cohort 4)
干预措施: Capmatinib (Drug)
Cohort 7 (expansion of Cohort 5b): Treatment-naïve with MET mutation regardless of MET GCN (1L)
Treatment-naïve patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as first line (1L) (expansion cohort of Cohort 5b)
干预措施: Capmatinib (Drug)
结局指标
主要结局
Overall Response Rate (ORR) by Blinded Independent Review Committee (BIRC) Assessment
时间窗: Up to approximately 5 years
Percentage of participants with a best overall response defined as confirmed complete response (CR) or partial response (PR) by BIRC assessment per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target and non-target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
次要结局
- ORR by Investigator Assessment(Up to approximately 5 years)
- Time to Response (TTR) by BIRC Assessment(Up to approximately 5 years)
- Duration of Response (DOR) by BIRC Assessment(Up to approximately 5 years)
- DOR by Investigator Assessment(Up to approximately 5 years)
- Disease Control Rate (DCR)(Up to approximately 5 years)
- Overall Survival (OS)(Up to approximately 6 years)
- Pharmacokinetic (PK) Concentrations of Capmatinib(Cycle (C) 1 Day (D) 1 predose and 2 hours post-dose, C1D15 pre-dose and 2 hours post-dose, C3D1 pre-dose. Each Cycle is 21 days)
- TTR by Investigator Assessment(Up to approximately 5 years)
- Maximum Concentration (Cmax) of Capmatinib(Cycle 1 Day 1 and Day 15 at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Each Cycle is 21 days)
- Maximum Concentration (Cmax) of CMN288(Cycle 1 Day 1 and Day 15 at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Each Cycle is 21 days)
- Area Under the Plasma Concentration-time Curve From Zero to Time Infinity (AUCinf) of Capmatinib(Cycle 1 Day 1 at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Each Cycle is 21 days)
- Area Under the Plasma Concentration-time Curve From Zero to Time Infinity (AUCinf) of CMN288(Cycle 1 Day 1 at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Each Cycle is 21 days)
- Progression-Free Survival(Up to approximately 5 years)
- Time to Reach Maximum Concentration (Tmax) of Capmatinib(Cycle 1 Day 1 and Day 15 at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Each Cycle is 21 days)
- Time to Reach Maximum Concentration (Tmax) of CMN288(Cycle 1 Day 1 and Day 15 at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Each Cycle is 21 days)
- Elimination Half-life (T1/2) of Capmatinib(Cycle 1 Day 1 and Day 15 at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Each Cycle is 21 days)
- Elimination Half-life (T1/2) of CMN288(Cycle 1 Day 1 and Day 15 at pre-dose, 0.5, 1, 2, 4, 6 and 8 hours post-dose. Each Cycle is 21 days)