Phase I/Ib Trial of Single Agent PBF-509 and in Combination With PDR001 for Patients With Advanced NSCLC
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 92
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of PBF-509 as single agent
研究概览
简要总结
The purpose of this study is to determine the safety, tolerability, feasibility and preliminary efficacy of the administration of PBF-509 (Adenosine A2a receptor antagonist) as single agent or in combination with PDR001 (programmed cell death 1 receptor antibody (PD-1 Ab)) to NSCLC patients.
详细描述
A single institution phase I/Ib (dose escalation plus expansion) clinical trial of PBF-509 and combination treatment of PDR001 plus PBF-509 in Eastern Cooperative Oncology Group (ECOG) 0-1 patients with immunotherapy naïve and pretreated, advanced or metastatic NSCLC will be conducted to evaluate the safety, tolerability and preliminary efficacy of the combination.
The main objectives of the proposed Phase I trial will be:
Phase I Dose Escalation:
- To determine the safety and tolerability of PBF-509 during a phase I dose escalation trial
- Determine the pharmacokinetic profile of PBF-509
- Determine the safety profile of PBF-509
Phase 1 Dose Expansion:
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
- •Patients must have histologic or cytologic diagnosis of advanced/metastatic NSCLC. For those with mixed histology, there must be a predominant histology.
- •Patients must previously have received at least one prior line of therapy for their disease
- •EGFR mutation with exon 19 deletion or L858R mutation (Exon 21) or ALK rearrangement positive must have failed prior TKI therapy
- •Able, willing to give written consent for available archival tumor samples (not mandatory) and tumor biopsies before and during protocol therapy (mandatory).
- •Prior immunotherapy is allowed (previous immune checkpoint inhibitors; anti-CTLA-4, anti-PD-1, anti-PD-L1 and/or combinations), except for the patients enrolled to the immunotherapy naïve group of the phase IB dose expansion.
- •Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral computed tomography (CT) scan, Magnetic resonance imaging (MRI), or calipers by clinical exam. See Section
- •Written informed consent and any locally-required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
- •Age > 18 years at time of study entry
- •Eastern Cooperative Oncology Group (ECOG) 0-1
- •Adequate normal organ and marrow function
- •Female patients must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old or no menses for 1 year without an alternative medical cause; OR history of complete hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use 2 highly effective methods of contraception while taking study treatment and for 90 days after the last dose of study treatment.
- •Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
排除标准
- •Symptomatic and/or untreated Brain Metastases
- •Pregnancy or breast feeding
- •Serious uncontrolled medical disorder or active infection that in the investigator's opinion would impair the patient's ability to receive study treatment.
- •Concurrent use of other anticancer approved or investigational agents is not allowed.
- •Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
- •Prior malignancy in past 2 years or as identified in Section 7.2 of this protocol
- •Patients receiving systemic steroids ≥ 10mg/day of prednisone or the equivalent
- •Smoking (cigarettes, cigars or pipes) must be discontinued at least 7 days prior to initiating study drug administration; smoking cessation products (transdermal nicotine patches or chewing gum may be used)
- •Concurrent administration of strong inhibitors or moderate inducers of CYP1A2 is not permitted; administration must be discontinued at least 7 days prior to initiating study drug administration.
研究组 & 干预措施
PBF-509_80 mg
干预措施: PBF-509_80 mg (Drug)
PBF-509_160 mg
干预措施: PBF-509_160 mg (Drug)
PBF-509_320 mg
干预措施: PBF-509_320 mg (Drug)
PBF-509_640 mg
干预措施: PBF-509_640 mg (Drug)
PBF509_160 mg +PDR001
干预措施: Combo PBF-509 (160 mg) + PDR001 (Drug)
PBF509_320 mg+PDR001
干预措施: Combo PBF-509 (320 mg) + PDR001 (Drug)
PBF509_640 mg +PDR001
干预措施: Combo PBF-509 (640 mg) + PDR001 (Drug)
RP2D (PBF-509+PDR001)_immuno naïve
Immunotherapy naïve patients will be treated at the combination RP2D previously determined in the phase Ib, dose escalation portion of the trial.
干预措施: RP2D (PBF-509+PDR001)_immuno naïve (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of PBF-509 as single agent
时间窗: 28 days
The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.
Maximum Tolerated Dose (MTD) of the combination (PBF-509+PDR001) treatment
时间窗: 56 days
The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PDR001 and PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.
次要结局
- Time to PBF-509 peak concentration in plasma at steady state "Tmax,ss"(8 days)
- The area under PBF-509 plasma concentration-time curve to infinite time "AUC(0-inf)"(8 days)
- PBF-509 half-life in plasma " t½"(8 days)
- Efficacy as measured by Disease control rate (DCR)(3 years)
- The area under PBF-509 plasma concentration-time curve up to time 't' "AUC(0-t)"(8 days)
- The PBF 509 accumulation index "Rac"(8 days)
- Efficacy as measured by duration of response (DoR)(3 years)
- Efficacy as measured by progression-free survival (PFS)(3 years)
- PBF-509 peak concentration in plasma "Cmax"(8 days)
- PBF-509 peak concentration in plasma at steady state"Cmax,ss"(8 days)
- Efficacy as measured by Objective response rate (ORR)(3 years)
- Time to PBF-509 peak concentration in plasma "Tmax"(8 days)
- PBF-509 total body clearance following extravascular administration "Cl/F"(8 days)
- The area under PBF-509 plasma concentration-time curve over the dosing interval "AUC(0-τ)"(8 days)
- PBF-509 apparent volume of distribution following extravascular administration"Vd/F"(8 days)
- Efficacy as measured by overall survival (OS)(3 years)