A Phase 1, Open-label, Dose Escalation Study To Evaluate Safety, Pharmacokinetics And Pharmacodynamics Of Combined Oral C-met/Alk Inhibitor (Pf-02341066) And Pan-her Inhibitor (Pf-00299804) In Patients With Advanced Non-small Cell Lung Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 70
- 试验地点
- 9
- 主要终点
- Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase
研究概览
简要总结
Lung cancer tumors become resistant to the first generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib by changing and increasing the activity of two cell signaling pathways: the cMET pathway and the EGFR pathway. Both resistance mechanisms can occur at the same time, in the same patient and even in the same tumor. This study combines a second generation EGFR inhibitor and a cMET inhibitor to block both these pathways in order to overcome resistance and treat this disease.
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
- •advanced non small cell lung cancer (dose escalation phase)
- •acquired resistance to erlotinib or gefitinib (expansion phase)
- •mandatory entrance biopsy (expansion phase)
排除标准
- •interstitial lung disease
- •unstable brain metastases
- •leptomeningeal disease
研究组 & 干预措施
Arm 1
PF-02341066 AND PF-00299804: Patients will be treated with combined cMET inhibitor (PF-02341066) and panHER inhibitor (PF-00299804).
干预措施: PF-02341066 (Drug)
Arm 1
PF-02341066 AND PF-00299804: Patients will be treated with combined cMET inhibitor (PF-02341066) and panHER inhibitor (PF-00299804).
干预措施: PF-00299804 (Drug)
Arm 2
PF-00299804 FOLLOWED BY COMBINED PF-02341066 AND PF-00299804: Patients will be treated with single agent panHER inhibitor (PF-00299804) until disease progression and then with the maximum tolerated combined dose of cMET inhibitor (PF-02341066) and panHER inhibitor (PF-00299804).
干预措施: PF-02341066 (Drug)
Arm 2
PF-00299804 FOLLOWED BY COMBINED PF-02341066 AND PF-00299804: Patients will be treated with single agent panHER inhibitor (PF-00299804) until disease progression and then with the maximum tolerated combined dose of cMET inhibitor (PF-02341066) and panHER inhibitor (PF-00299804).
干预措施: PF-00299804 (Drug)
结局指标
主要结局
Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase
时间窗: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)
An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase
时间窗: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)
AE was any untoward medical occurrence with study drug/ device in a trial participant. Serious adverse event (SAE) was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Overview of Treatment-emergent All Causalities AEs in Expansion Phase
时间窗: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)
AE was any untoward medical occurrence with study drug/ device in a trial participant. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase
时间窗: Cycle 1 (4 weeks)
DLTs were those AEs which occurred in Cycle 1 of treatment in Dose Escalation Phase which may be attributed to study drug \[combined Crizotinib (PF-02341066) plus Dacomitinib (PF-00299804)\] without a clear alternative explanation and despite the use of adequate/maximal medical intervention as dictated by local institutional clinical practices or the judgment of the investigator. The following events were considered DLTs (using CTCAE version 4.02);1. Grade ≥4 hematologic events. 2. Grade ≥3 non-hematological events (except Grade 3/4 asymptomatic hypophosphatemia and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea had to have persisted at Grade 3 or 4 despite maximal medical therapy. Grade 3 hypertension will be considered a DLT only if the event is unmanageable by standard approved pharmacologic agents or if the symptomatic sequelae are identified despite appropriate medical intervention.
Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase
时间窗: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)
An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
次要结局
- Duration of Response for the Only Participant Shown Partial Response in Expansion Phase(From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment))
- Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase(From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment))
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10)(C1D1, C1D15)
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast)(C1D1, C1D15)
- Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase(From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment))
- Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method(Baseline)
- Number of Participants With KRAS Mutation (GLY12CYS) at Baseline(Baseline)
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax)(C1D1, C1D15)
- Number of Participants With Objective Response Rate (ORR) in Escalation Phase(From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment))
- Number of Participants With EGFR Mutation at Baseline(Baseline)
- Number of Participants With PIK3CA Mutation at Baseline(Baseline)
- Progression Free Survival (PFS) in Escalation Phase(From randomization to objective tumor progression or death (up to post treatment follow-up as 28-35 days after last dose of study treatment))
- Progression Free Survival (PFS) in Expansion Phase(From randomization to objective tumor progression or death (up to post treatment follow-up as 28-35 days after last dose of study treatment))
- Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method(Baseline)
- Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method(Baseline)
- Plasma Concentration of sMet by Study Visits(At screening and Cycle 1 Day 1 (C1D1) (6 hours post dose), and C1D15, C2D1, C2D15 (all predose).)
- Number of Participants With ROS1 Gene Translocation at Baseline(Baseline)
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Concentration (AUClast)(Cycle 1 (C1)/Day 1 (D1), C1D15)
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast(C1D1, C1D15)
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24(C1D1, C1D15)
- Number of Participants With ORR in Expansion Phase(From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment))
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast(Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax(Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax(Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax(C1D1, C1D15)
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast(C1D1, C1D15)
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24(Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax(Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax(Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax)(C1D1, C1D15)
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax(C1D1, C1D15)
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10(Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast(Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast(Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin(Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast(Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib))
- Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin(Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib))