NCT00927823已完成1 期
A Phase 1, Open-Label, Dose-Escalation Study To Evaluate Safety, Pharmacokinetics, And Pharmacodynamics Of The PI3K/MTOR Inhibitor PF-04691502 In Adult Patients With Advanced Malignant Solid Tumors
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
研究概览
简要总结
A phase 1 dose-escalation trial to assess the safety, tolerability, and pharmacodynamics of PF-04691502 in adult cancer patients with solid tumors.
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 with a histologically or cytologically confirmed malignant solid tumor for which there is no currently approved treatment or which is unresponsive to currently approved therapies.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1
- •Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours of the first dose of PF-04961502, These patients or their partners must be surgically sterile or be postmenopausal, or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter. Male patients or their partners must be surgically sterile or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate
- •Adequate Bone Marrow Function, including:
- •Absolute neutrophil count (ANC) ≥1500 cells/mm3
- •Platelets ≥75,000 cells/mm3
- •Hemoglobin ≥9 mg/dL
- •Adequate Renal Function, including:
- •SrCr <1.5 x ULN (upper limit of normal). OR Estimated creatinine clearance ≥60 mL/min, as calculated using method standard for the institution
- •Adequate Liver Function, including:
- •Bilirubin ≤1.5 x ULN AST (SGOT) ≤2.5 x ULN ALT (SGPT) ≤2.5 x ULN
- •Adequate glucose control, including no previous diagnosis of diabetes mellitus and HbA1c <7%.
- •Adequate Cardiac Function, including:
- •12-Lead electrocardiogram (ECG) with normal tracing or non clinically significant changes that do not require medical intervention. QTc interval ≤470 msec and no history of Torsades des Pointes or other symptomatic QTc abnormality
排除标准
- •Patients with known active brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable
- •Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions), biological or investigational agents within 2 weeks of Baseline disease assessments
- •Any surgery (not including minor procedures such as lymph node biopsy) within 4 weeks of Baseline disease assessments; or not fully recovered from any side effects of previous procedures
- •Prior therapy with an agent that is known or proposed to be active by action on PI3K and/or mTOR
- •Prior high-dose chemotherapy requiring hematopoetic stem cell transplantation within 12 months of study treatment start
- •Uncontrolled or significant cardiovascular disease:
- •A myocardial infarction within 12 months Uncontrolled angina within 6 months Congestive heart failure within 6 months. Diagnosed or suspected congenital long QT syndrome. Any history of ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). Any history of second or third degree heart block (may be eligible if currently have a pacemaker) Heart rate <50/minute on pre-entry electrocardiogram Uncontrolled hypertension.
- •Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors or inducers
- •Current use or anticipated need for food or drugs that are known potent CYP1A2 inhibitors or inducers
- •Concurrent administration of herbal preparations
- •Breast feeding: No studies have been conducted in humans to assess the impact of PF-04691502 on milk production, its presence in breast milk and its effects on the breast-fed child. Because drugs are commonly excreted in human milk and because of the potential for serious adverse reactions in nursing infants, lactating female patients are excluded from this study.
- •Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet form and malabsorption syndrome.
- •Any mental disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol
研究组 & 干预措施
PF-04691502 Treatment
Experimental
干预措施: PF-04691502 (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
时间窗: Baseline up to 28 days after the last dose
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Baseline up to Cycle 1 Day 21
DLT was classified as per common terminology criteria for adverse events (CTCAE) version 4.0 and defined as any of the following events occurring after first dose of study medication and considered at least possibly-related to study medication. Hematological: grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cells per cubic millimeter \[cells/mm\^3\]) for 1 week or greater, febrile neutropenia (fever \>=38.5 degree celsius with ANC \<1000/mm\^3), grade 3 (50,000 cells/mm\^3) and grade 4 (\<25,000 cells/mm\^3) thrombocytopenia; Non-Hematologic: grade 3 or 4 nausea, vomiting, or diarrhea and any clinically significant grade 3 or greater non-hematologic toxicity, despite the use of adequate/maximal medical intervention and/or prophylaxis, and any persistent, intolerable PF-04691502 related toxicity which delayed retreatment for \>14 days.
Recommended Phase-2 Dose (RP2D)
时间窗: Baseline up to Cycle 1 Day 21
RP2D was determined based on the safety profile and pharmacodynamic findings, as per investigator's discretion.
次要结局
- Number of Participants With Maximum Post-dose QT Interval Corrected Using Fridericia's Formula (QTcF)(Pre-dose, 30 minutes, 1, 2, 4, 8, 24, 48, hrs post-dose in Lead-in period; 1 hour post-dose on C1D8, C1D15; 1, 2, 4, 8 hours post-dose on C1D21; 1 hour post-dose C2D1, C2D15, D1 of subsequent cycles up to C8; EOT)
- Change From Baseline in Serum Glucose at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT)(Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT)
- Maximum Observed Plasma Concentration (Cmax)(Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hours post-dose on Cycle 1 Day 21 (C1D21))
- Time to Reach Maximum Observed Plasma Concentration (Tmax)(Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hours post-dose on C1D21)
- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)(Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period)
- Plasma Decay Half-Life (t1/2)(Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours (hrs) post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hrs post-dose on C1D21)
- Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)](Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period)
- Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)(Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hrs post-dose on C1D21)
- Number of Participants With Increase From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF)(Pre-dose, 30 minutes, 1, 2, 4, 8, 24, 48, hrs post-dose in Lead-in period; 1 hour post-dose on C1D8, C1D15; 1, 2, 4, 8 hours post-dose on C1D21; 1 hour post-dose C2D1, C2D15, D1 of subsequent cycles up to C8; EOT)
- Change From Baseline in Serum Insulin at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT)(Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT)
- Change From Baseline in Serum C-peptide at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT)(Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT)
- Change From Baseline in Fresh Tumor Biopsy Biomarkers at Cycle 1 Day 21(Baseline; 4 hours post-dose on C1D21)
- Change From Baseline in Hair Follicle Biopsy Biomarkers at Cycle 1 Day 21(Baseline; pre-dose, 2, 4, 24 hours post-dose on C1D21)
- Number of Participants With Mutation, Deletion, Amplification in Phosphatidylinositol 3-kinase (PI3K) Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue(Baseline; 4 hours post-dose on C1D21)
- Number of Participants With Objective Response(Baseline, prior to Day 1 of Cycle every odd-numbered cycle or when progressive disease was suspected)
研究者
研究点 (1)
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