A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 177
- 试验地点
- 2
- 主要终点
- Phase II Group 1, 2 and 3: Overall Response Rate (ORR) by Investigator's Assessment Per RECIST 1.1
研究概览
简要总结
The purpose of this study was to determine the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) of nazartinib (EGF816) in combination with capmatinib (INC280) and to estimate the preliminary anti-tumor activity of nazartinib in combination with capmatinib in participants with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.
详细描述
This study was designed as a Phase Ib/II, multi-center, open-label study starting with a Phase Ib dose escalation part followed by a Phase II expansion part. Oral nazartinib (once daily) and capmatinib (twice daily) was administered on a continuous schedule until participant experienced unacceptable toxicity, progressive disease (PD) and/or treatment was discontinued at the discretion of the investigator or withdrawal of consent/opposition to use data/biological samples. Study treatment could be continued beyond Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) defined PD, in the judgment of the investigator, when there was evidence of clinical benefit and the subject wished to continue with the study treatment.
In Phase Ib part, participants with NSCLC harboring EGFR activating mutations were enrolled. At the end of the Phase Ib part, once the MTD or RP2D of nazartinib in combination with capmatinib was declared, additional participants with NSCLC were enrolled in the Phase II part in order to assess the preliminary anti-tumor activity of nazartinib in combination with capmatinib. Participants with locally advanced or metastatic NSCLC were assigned into different groups according to their resistance mechanisms.
As per the Protocol amendment 7, an additional group (Group 5) was included into study CINC280X2105C, which was intended to support study CINC280L12301. After thorough and careful assessment of study CINC280L12301 enrollment status, projected study completion timelines, and the changing clinical landscape, Novartis made the decision to discontinue the study. Importantly, this decision was not driven by safety concerns; no new safety signals were observed in the study participants or in the ongoing capmatinib program. As such, Group 5 data was no longer needed and the new arm in study CINC280X2105C was not opened as planned.
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase IB part- NSCLC with EGFR activating mutations
NSCLC participants who have previously documented EGFR mutation and progressed on EGFR TKI treatment. Participants were treated at a starting dose of 50 mg once a day for EGF816 and 200 mg twice a day for INC280 in fasted state
干预措施: Capmatinib (Drug)
Phase IB part- NSCLC with EGFR activating mutations
NSCLC participants who have previously documented EGFR mutation and progressed on EGFR TKI treatment. Participants were treated at a starting dose of 50 mg once a day for EGF816 and 200 mg twice a day for INC280 in fasted state
干预措施: Nazartinib (Drug)
Phase II- Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant)
NSCLC participants with previously documented activating EGFR mutation, with any T790M and MET dysregulation status, who received one to three lines of systemic antineoplastic therapy prior to study entry including one line maximum of first or second generation EGFR TKI and who progressed on this EGFR TKI treatment line. Participants were treated at the RP2D of INC280 and EGF816 in fasted state
干预措施: Capmatinib (Drug)
Phase II- Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant)
NSCLC participants with previously documented activating EGFR mutation, with any T790M and MET dysregulation status, who received one to three lines of systemic antineoplastic therapy prior to study entry including one line maximum of first or second generation EGFR TKI and who progressed on this EGFR TKI treatment line. Participants were treated at the RP2D of INC280 and EGF816 in fasted state
干预措施: Nazartinib (Drug)
Phase II- Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve)
NSCLC participants harboring T790M mutation in de novo setting, irrespective of the activating mutation status who are treatment naïve or received maximum 2 lines of systemic antineoplastic therapy prior to study entry, but no therapy known to inhibit EGFR. Participants were treated at the RP2D of INC280 and EGF816 in fasted state
干预措施: Capmatinib (Drug)
Phase II- Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve)
NSCLC participants harboring T790M mutation in de novo setting, irrespective of the activating mutation status who are treatment naïve or received maximum 2 lines of systemic antineoplastic therapy prior to study entry, but no therapy known to inhibit EGFR. Participants were treated at the RP2D of INC280 and EGF816 in fasted state
干预措施: Nazartinib (Drug)
Phase II- Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic)
NSCLC participants with previously documented EGFR activating mutation, T790M negative, and any MET status who never received any prior line of systemic antineoplastic systemic therapy prior to study entry. Participants were treated at the RP2D of INC280 and EGF816 in fasted state
干预措施: Capmatinib (Drug)
Phase II- Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic)
NSCLC participants with previously documented EGFR activating mutation, T790M negative, and any MET status who never received any prior line of systemic antineoplastic systemic therapy prior to study entry. Participants were treated at the RP2D of INC280 and EGF816 in fasted state
干预措施: Nazartinib (Drug)
Phase II- Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic)
NSCLC participants with previously documented EGFR activating mutations and any T790M and MET status who were treatment naïve or failed maximum 2 prior lines of any systemic antineoplastic therapy for advanced disease. Participants were treated at the RP2D of INC280 and EGF816 in fed state
干预措施: Capmatinib (Drug)
Phase II- Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic)
NSCLC participants with previously documented EGFR activating mutations and any T790M and MET status who were treatment naïve or failed maximum 2 prior lines of any systemic antineoplastic therapy for advanced disease. Participants were treated at the RP2D of INC280 and EGF816 in fed state
干预措施: Nazartinib (Drug)
Phase II- Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI resistant)
NSCLC participants with previously documented EGFR activating mutation, T790M negative, acquired MET amplification who have progressed on one prior line of therapy for advanced/metastatic NSCLC disease. Participants were to start with INC280 monotherapy (twice a day) and would have had the opportunity to continue to combination of EGF816 (once a day) and INC280 (twice a day) based on radiological disease progression evaluation by investigator's assessment per RECIST 1.1
干预措施: Capmatinib (Drug)
Phase II- Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI resistant)
NSCLC participants with previously documented EGFR activating mutation, T790M negative, acquired MET amplification who have progressed on one prior line of therapy for advanced/metastatic NSCLC disease. Participants were to start with INC280 monotherapy (twice a day) and would have had the opportunity to continue to combination of EGF816 (once a day) and INC280 (twice a day) based on radiological disease progression evaluation by investigator's assessment per RECIST 1.1
干预措施: Nazartinib (Drug)
结局指标
主要结局
Phase II Group 1, 2 and 3: Overall Response Rate (ORR) by Investigator's Assessment Per RECIST 1.1
时间窗: Up to approximately 4 years
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) determined by investigator's assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). ORR was assessed in Group 1, 2 and 3 (Phase II part). CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.
Phase II Group 4: Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
时间窗: From start of treatment up to 30 days after last dose of study treatment, assessed up to 3.7 years
Number of participants in Group 4 (Phase II part) with AEs and SAEs. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward event resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.
Phase II Group 4: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618
时间窗: From start of treatment until end of treatment, assessed up to 3.6 years
Number of participants with at least one dose reduction of INC280, at least one dose interruption of INC280, at least one dose reduction of EGF816 and at least one dose interruption of EGF816 in the Group 4 (Phase II part).
Phase II Group 4: Dose Intensity
时间窗: From start of treatment until end of treatment, assessed up to 3.6 years
Dose intensity, defined as the ratio of total dose received and actual duration, for participants in Group 4 (Phase II part)
Phase II Group 5: ORR Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy
时间窗: Up to approximately 3 years (while on INC280 monotherapy)
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for participants in Group 5 (Phase II part) while on treatment with INC280 monotherapy. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters.
Phase Ib: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Up to first 28 days of treatment
Number of participants with DLTs in the Phase Ib part. A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment with EGF816 in combination with INC280 during the escalation part of the study (Phase Ib)
次要结局
- Phase Ib: Time to Reach Maximum Concentration (Tmax) of EGF816(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days))
- Phase Ib: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment(Up to approximately 5 years)
- Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618(From start of treatment until end of treatment, assessed up to approximately 5 years)
- Phase II Group 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618(From start of treatment until end of treatment, assessed up to approximately 4 years)
- Phase Ib: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment(From date of first dose to first documented disease progression or death, assessed up to approximately 5 years)
- Phase Ib: Dose Intensity(From start of treatment until end of treatment, assessed up to approximately 5 years)
- Phase II Group 1, 2 and 3: Dose Intensity(From start of treatment until end of treatment, assessed up to approximately 4 years)
- Phase Ib: Overall Response Rate (ORR) Per RECIST 1.1 Based on Investigator's Assessment(Up to approximately 5 years)
- Phase II Group 4: Overall Response Rate (ORR) Per RECIST 1.1 Based on Investigator's Assessment(Up to approximately 4 years)
- Phase II Groups 1, 2, 3 and 4: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment(From date of first dose to first documented disease progression or death, assessed up to approximately 4 years)
- Phase Ib: Time to Response (TTR) Per RECIST 1.1 Based on Investigator's Assessment(From the date of the first dose to the date of first documented response, up to approximately 5 years)
- Phase II Groups 1, 2, 3 and 4: Time to Response (TTR) Per RECIST 1.1 Based on Investigator's Assessment(From the date of the first dose to the date of first documented response, up to approximately 4 years)
- Phase Ib: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment(From date of first documented response to first documented disease progression or death, assessed up to approximately 5 years)
- Phase II Groups 1, 2, 3 and 4: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment(From date of first documented response to first documented disease progression or deaths, assessed up to approximately 4 years)
- Phase II Group 1, 2 3 and 4: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment(Up to approximately 4 years)
- Phase II Groups 3 and 4: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 12 Hours (AUC0-12) of INC280(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days))
- Phase II Groups 3 and 4: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of EGF816(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days))
- Phase Ib: Overall Survival (OS)(From date of first dose to death, assessed up to approximately 5 years)
- Phase II Groups 1, 2, 3 and 4: Overall Survival (OS)(From date of first dose to death, assessed up to approximately 4 years)
- Phase Ib: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 12 Hours (AUC0-12) of INC280(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days))
- Phase Ib: Peak Plasma Concentration (Cmax) of INC280(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days))
- Phase Ib: Time to Reach Maximum Concentration (Tmax) of INC280(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days))
- Phase II Groups 3 and 4: Peak Plasma Concentration (Cmax) of INC280(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days))
- Phase II Groups 3 and 4: Time to Reach Maximum Concentration (Tmax) of INC280(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days))
- Phase Ib: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of EGF816(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days))
- Phase Ib: Peak Plasma Concentration (Cmax) of EGF816(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days))
- Phase II Groups 3 and 4: Peak Plasma Concentration (Cmax) of EGF816(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days))
- Phase II Groups 3 and 4: Time to Reach Maximum Concentration (Tmax) of EGF816(Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days))
- Phase II Group 5: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy(Up to approximately 3 years (while on INC280 monotherapy))
- Phase II Group 5: Number of Participants With Dose Modifications for INC280 Monotherapy as Well as INC280 in Combination With EGF816 Therapy(From start of treatment until end of treatment, up to approximately 3 years)
- Phase II Group 5: Dose Intensity for INC280 Monotherapy as Well as INC280 in Combination With EGF816 Therapy(From start of treatment until end of treatment, up to approximately 3 years)
- Phase II Group 5: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy(From date of first documented response to the date of first documented disease progression or death, assessed up to approximately 3 years (while on INC280 monotherapy))
- Phase II Group 5: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy(Up to approximately 3 years (while on INC280 monotherapy))