A Phase 1b/2 Study of the Safety and Efficacy of Rociletinib (CO-1686) Administered in Combination With MPDL3280A in Patients With Activating EGFR Mutation-positive (EGFRm) Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Minimum Concentration (Cmin) of Rociletinib and Metabolites
研究概览
简要总结
This clinical research study is being carried out in two parts, Phase 1 and Phase 2. The primary purpose of the Phase 1 portion of the study is to observe the safety of the combination of rociletinib and MPDL3280A in EGFR-mutant NSCLC patients.
The primary purpose of the Phase 2 portion of the study is to evaluate the safety and anti-tumor effects of the combination of rociletinib and MPDL3280A, at the best doses for the combination determined in Phase 1, in patients with EGFR-mutant NSCLC.
详细描述
This is a Phase 1b/2, open-label, non-randomized, multicenter study evaluating the safety and efficacy of rociletinib administered in combination with MPDL3280A.
Phase 1: This will be the dose finding phase of the study. Patients will be enrolled to available Dosing Cohort. Patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status, will be enrolled.
Phase 2: Patients will be enrolled into 2 groups. Group A will enroll eligible first-line patients who are EGFR TKI treatment-naïve and chemotherapy-naïve. Group B will enroll eligible patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status.
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
- •ECOG performance status of 0 or 1
- •Adequate hematological and biological function, confirmed by defined laboratory values
- •Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion
- •Measurable disease as defined by RECIST v1.1
- •Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment
- •For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). Previous chemotherapy for NSCLC is allowed.
- •For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve
排除标准
- •Unresolved toxicities from prior therapy
- •Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases
- •Previous treatment with rociletinib or MPDL3280A, or other 3rd generation EGFR TKI (eg, AZD-9291, HM61713), or PD 1 axis targeted therapy (eg, anti PD 1 or anti-PD L1)
- •Prior treatment with CD137 agonists or other immune checkpoint blockade therapies, including anti-CTLA-4 therapeutic antibodies
- •Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures
- •Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab (bisphosphonate use for prevention of skeletal events allowed)
- •Known hypersensitivity to any component of the MPDL3280A or rociletinib formulations or history or hypersensitivity to chimeric humanized antibodies or fusion proteins
- •History of autoimmune disease
- •History of prior allogeneic hematopoietic stem cell transplantation or prior solid organ transplantation
- •Treatment with systemic immunosuppressive medications within 2 weeks prior to first day of study treatment (inhaled corticosteroids and mineralocorticoids allowed)
- •Live attenuated vaccine within 4 weeks prior to first day of study treatment
- •Active tuberculosis, active hepatitis, or positive HIV status
- •Class II to IV heart failure as defined by the New York Heart Association functional classification system
- •Untreated or uncontrolled cardiovascular disease or other symptomatic cardiac dysfunction
- •QTCF > 450 ms, inability to measure QT interval on ECG, personal or family history of long QT syndrome, requirement for medications that have the potential to prolong the QT interval
- •History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan (history of radiation pneumonitis in radiation field may be allowed)
- •Other malignancies within 5 years prior to enrollment, with the exception of carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ
研究组 & 干预措施
Single Arm Rociletinib and MPDL3280A
Specific doses of rociletinib, taken continuously BID, will be administered in combination with a fixed dose of MPDL3280A, given intravenously on Day 1 of each 21-day cycle.
干预措施: Rociletinib (Drug)
Single Arm Rociletinib and MPDL3280A
Specific doses of rociletinib, taken continuously BID, will be administered in combination with a fixed dose of MPDL3280A, given intravenously on Day 1 of each 21-day cycle.
干预措施: MPDL3280A (Drug)
结局指标
主要结局
Minimum Concentration (Cmin) of Rociletinib and Metabolites
时间窗: Approximately every 6 weeks up to 24 months
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites
时间窗: Treatment Day 1 and Day 8
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. AUC0 24 will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03
时间窗: Continuously, up to approximately 18.5 months
The safety analyses will be performed using the safety population. Safety data analysis will be conducted on all patients receiving at least one dose of rociletinib or MPDL3280A.
Maximum Concentration (Cmax) of Rociletinib and Its Metabolites
时间窗: Treatment Day 1 and Day 15
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites
时间窗: Treatment Day 1 and Day 15
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Tmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Maximum Concentration (Cmax) of MPDL3280A
时间窗: Cycle 1 Day 1
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax, for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Minimum Concentration (Cmin) of MPDL3280A
时间窗: Approximately every 6 weeks up to 24 months
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Objective Response Rate Per RECIST v1.1 in Phase 2
时间窗: Approximately every 6-9 weeks
To determine the efficacy of the combination of rociletinib and MPDL3280A based on overall response rate per RECIST v1.1 in the following groups of patients: * Group A: Patients with EGFRm advanced or metastatic NSCLC who have not previously received an EGFR TKI or chemotherapy. * Group B: Patients with EGFRm advanced or metastatic NSCLC who have progressed on a prior EGFR TKI.
次要结局
- Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2(Approximately every 6-9 weeks, up to 24 months)
- Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2(Approximately every 6-9 weeks, up to 24 months)
- Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2(Approximately every 6-9 weeks, up to 24 months)
- Number of Patients Alive at Study Termination(Up to approximately 18.5 months)
- Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA(Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months)