A Phase I, Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3326595 in Subjects With Solid Tumors and Non-Hodgkin's Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 297
- 试验地点
- 1
- 主要终点
- Part 1: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
This first time in human (FTIH) open-label, dose escalation study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK3326595 in participants with advanced or recurrent solid tumors, as well as clinical activity in participants with a subset of solid tumors and non-Hodgkin's lymphoma (NHL).
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
盲法说明
This is an open label study.
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
- •Malignancy attributed to prior solid organ transplant
- •Leptomeningeal disease, spinal cord compression, or brain metastases that require immediate central nervous system (CNS)-specific treatment in the opinion of the Investigator (for example [e.g.], for symptomatic disease)
- •History of a second malignancy, excluding non-melanoma skin cell cancer within the last three years
- •Evidence of severe or uncontrolled systemic diseases, or serious and/or pre-existing medical or other condition that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator
- •Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
- •Select cardiac abnormalities (as defined in the protocol)
- •History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
- •History of optic nerve neuropathy or neuritis.
研究组 & 干预措施
Part 1: Dose Escalation, Food effect and Relative Bioavailability of Capsule formulation to Tablet
Participants will receive escalating doses of GSK3326595 until the maximum tolerated dose level is reached. The recommended phase 2 dose (RP2D) will be determined. Participants will be dosed in a fed (high-fat, high-calorie meal) and fasted state to determine the effect of food on bioavailability of GSK3326595, and will be dosed with tablet and capsule to compare two formulations of GSK3326595 (capsule versus tablet).
干预措施: GSK3326595 (Drug)
Part 2: Disease-Specific Expansion cohort
Participants with triple-negative breast cancer (TNBC), metastatic transitional cell carcinoma of the urinary system (mTCC), Grade IV anaplastic astrocytoma (glioblastoma multiforme [GBM]), non-Hodgkin's lymphoma (NHL), adenoid cystic carcinoma (ACC), hormone receptor-positive adenocarcinoma of the breast (ER+BC), human papillomavirus (HPV)-positive solid tumors of any histology, and p53-wild type non-small cell lung cancer (NSCLC) will be administered GSK3326595 at the recommended phase 2 dose (RP2D) as determined in Part 1.
干预措施: GSK3326595 (Drug)
Part 3: GSK3326595 in combination with pembrolizumab
Participants with selected solid tumors will be administered GSK3326595 in combination with pembrolizumab as part of this dose determination study.
干预措施: GSK3326595 (Drug)
Part 3: GSK3326595 in combination with pembrolizumab
Participants with selected solid tumors will be administered GSK3326595 in combination with pembrolizumab as part of this dose determination study.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Part 1: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Up to 30 months
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. A summary of number of participants with any AEs and SAEs is presented. AEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA dictionary).
Part 1: Number of Participants Withdrawn Due to AEs
时间窗: Up to 30 months
The data for number of participants withdrawn due to AEs have been presented.
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Up to 21 days
DLT is considered to be clinically relevant AE by investigator if it met at least one of the criteria: Grade(G)3 neutropenia for \>=5 days/G4 neutropenia of any duration, G3 or greater febrile neutropenia, G4 or greater anemia of any duration and thrombocytopenia, or G3 thrombocytopenia with bleeding, Alanine aminotransferase (ALT) \>3x upper limit of normal (ULN)+bilirubin, \>=2xULN or ALT between 3-5 X ULN with bilirubin \< 2Xuln but with hepatitis symptoms/rash, G3 nausea/vomiting/diarrhea that does not improve within 72 hour, G4 or greater nausea/vomiting/diarrhea, G3 or greater hypertension, G3 or greater clinically significant non-hematologic toxicity per National Cancer Institute -- Common Terminology Criteria for Adverse Events (NCICTCAE), Inability to receive at least 80% of scheduled doses in the DLT observation period due to toxicity, G2 or higher toxicity that occurs beyond 21 days which in the judgment of the investigator and GSK Medical Monitor was considered to be a DLT.
Part 1: Number of Participants With Dose Modifications of GSK3326595
时间窗: Up to 30 months
The number of participants who experienced any dose modifications (interruptions and reductions) of GSK3326595 have been presented.
Part 1: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
时间窗: Baseline (Day 1) and up to 30 months
Blood samples were collected for evaluation of clinical chemistry parameters. The summaries of worst-case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.
Part 1: Number of Participants With Worst Case Change From Baseline in Hematology Parameters
时间窗: Baseline (Day 1) and up to 30 months
Blood samples were collected for evaluation of hematology parameters. The summaries of worst-case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.
Part 1: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters
时间窗: Baseline (Day 1) and up to 30 months
Blood samples were collected for evaluation of coagulation parameters. The summaries of worst-case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v4.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.
Part 1: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters
时间窗: Baseline (Day 1) and up to 30 months
Urine samples were collected for evaluation of urinalysis parameters. The summaries of worst-case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with no change or change to negative and change to positive have been presented.
Part 1: Changes From Baseline in Urine Specific Gravity
时间窗: Baseline (Day 1) and up to week 132
Urine samples were collected from participants to assess urine specific gravity.
Part 1: Changes From Baseline in Urine Potential of Hydrogen (pH)
时间窗: Baseline (Day 1) and up to week 132
Urine samples were collected from participants to assess urine pH levels.
Part 1: Number of Participants With Maximum Grade Worst Case Increase Post-baseline Relative to Baseline in Vital Signs
时间窗: Baseline (Day 1) and up to 30 months
The abnormal vital sign ranges are: Heart Rate:- Low (\<60 beats per minute (bpm)), Normal (\>=60 bpm to \<=100 bpm), High (\>100 bpm); Temperature:- Low (\<=35 degree Celsius (°C)), Normal (\>35 °C and \<38 °C), High (\>=38 °C); Systolic Blood Pressure:- Low (\<90 millimeter of mercury (mmHg)), Normal (\>=90 mmHg to \<120 mmHg), High (\>=120 mmHg); Diastolic Blood Pressure:- Low (\<60 mmHg), Normal (\>=60 mmHg to \<80 mmHg), High (\>=80 mmHg). Participants were counted in the worst-case category and their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.
Part 3: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Up to 10 months
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or was a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. A summary of number of participants with any AEs and SAEs is presented. AEs were coded using the MedDRA dictionary.
Part 3: Number of Participants Withdrawn Due to AEs
时间窗: Up to 10 months
The data for number of participants withdrawn due to AEs have been presented.
Part 3: Number of Participants With Dose Modifications of GSK3326595 and Pembrolizumab
时间窗: Up to 10 months
The number of participants who experienced any dose modifications (interruptions and reductions) of GSK3326595 and pembrolizumab have been presented.
Part 3: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
时间窗: Baseline (Day 1) and up to 10 months
Blood samples were collected for evaluation of clinical chemistry parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented.
Part 3: Number of Participants With Worst Case Change From Baseline in Hematology Parameters
时间窗: Baseline (Day 1) and up to 10 months
Blood samples were collected for evaluation of hematology parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented.
Part 3: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters
时间窗: Baseline (Day 1) and up to 10 months
Blood samples were collected for evaluation of coagulation parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented.
Part 3: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters
时间窗: Baseline (Day 1) and up to 10 months
Urine samples were collected for evaluation of urinalysis parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with no change or change to negative and change to positive values have been presented.
Part 3: Changes From Baseline in Urine Potential of Hydrogen (pH)
时间窗: Baseline (Day 1) and up to Week 42
Urine samples were collected from participants to assess urine pH levels.
Part 3: Changes From Baseline in Urine Specific Gravity
时间窗: Baseline (Day 1) and up to Week 42
Urine samples were collected from participants to assess urine specific gravity.
Part 3: Number of Participants With Maximum Worst-case Increase Post-baseline Relative to Baseline in Vital Signs
时间窗: Baseline (Day 1) and up to 10 months
The abnormal vital sign ranges are: Heart Rate:- Low \[\<60 bpm\], Normal (\>=60 bpm to \<=100 bpm), High (\>100 bpm); Temperature:- Low (\<=35 C), Normal (\>35 C and \<38 C), High (\>=38 C); Systolic Blood Pressure:- Low (\<90 mmHg), Normal (\>=90 mmHg to \<120 mmHg), High (\>=120 mmHg); Diastolic Blood Pressure:- Low (\<60 mmHg), Normal (\>=60 mmHg to \<80 mmHg), High (\>=80 mmHg). Participants were counted in the maximum worst case increase category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.
次要结局
- Part 2: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to 42 months)
- Part 2: Number of Participants Withdrawn Due to AEs(Up to 42 months)
- Part 2: Number of Participants With Dose Modifications of GSK3326595(Up to 42 months)
- Part 2: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters(Baseline (Day 1) and up to 42 months)
- Part 2: Number of Participants With Worst Case Change From Baseline in Hematology Parameters(Baseline (Day 1) and up to 42 months)
- Part 2: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters(Baseline (Day 1) and up to 42 months)
- Part 2: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters(Baseline (Day 1) and up to 42 months)
- Part 2: Changes From Baseline in Urine Potential of Hydrogen (pH)(Baseline (Day 1) and up to week 184)
- Part 1: Area Under the Plasma Concentration-time Curve (AUC) Extrapolated From Time Zero to Infinity (AUC[0-inf]) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h post-dose)
- Part 2: Changes From Baseline in Urine Specific Gravity(Baseline (Day 1) and up to week 184)
- Part 2: Number of Participants With Maximum Grade Worst Case Increase Post-baseline Relative to Baseline in Vital Signs(Baseline (Day 1) and up to 42 months)
- Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours (h) post-dose; pre-dose on day 8; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose on day 15)
- Part 3: Maximum Observed Plasma Concentration (Cmax) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 3: Area Under the Plasma Concentration-time Curve (AUC) Extrapolated From Time Zero to Infinity (AUC[0-inf]) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 3: AUC From Time Zero to the Last Quantifiable Concentration After Dosing (AUC[0-t]) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 1: AUC From Time Zero to the Last Quantifiable Concentration After Dosing (AUC[0-t]) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 h post-dose; pre-dose on day 8; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose on day 15)
- Part 1: AUC Over the Dosing Interval Tau (AUC[0-tau]) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 h post-dose; pre-dose on day 8; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose on day 15)
- Part 3: AUC Over the Dosing Interval Tau (AUC[0-tau]) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 1: Terminal Phase Half-life (t1/2) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 h post-dose; pre-dose on day 8; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose on day 15)
- Part 3: Terminal Phase Half-life (t1/2) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 1: Oral Clearance (CL/F) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 3: Oral Clearance (CL/F) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 1: Accumulation Ratio (AR) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose on Day 1 and Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose on Day 15)
- Part 3: Accumulation Ratio (AR) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 1: Time Invariance (TI) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose on Day 1 and Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose on Day 15)
- Part 3: Time Invariance (TI) of GSK3326595(Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose)
- Part 1: Overall Response Rate (ORR) Based on RECIST 1.1(Up to 30 months)
- Part 2: Overall Response Rate (ORR) (Non-glioblastoma Multiforme [GBM] Cohorts)(Up to 42 months)
- Part 2: Six-month Progression Free Survival (PFS) Rate (GBM Cohort)(At month 6)
- Part 2: Duration of Response (DOR) (ACC Tablet Cohort)(Up to 42 months)
- Part 3: ORR Based on Immune-based RECIST (iRECIST) Criteria(Up to 10 months)
- Part 2: ORR (GBM Cohort) Based on Response Assessment Neuro-Oncology (RANO) Working Group Criteria(Up to 42 months)
- Part 2: ORR (Non-Hodgkin's Lymphoma (NHL) Cohorts) Based on Lugano Criteria(Up to 42 months)
- Part 2: Overall Survival (OS) (ACC Tablet Cohort)(Up to 42 months)
- Part 2: Progression-free Survival(Up to 42 months)
- RP2D Phase: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to maximum 42 months)
- RP2D Phase: Number of Participants Withdrawn Due to AEs(Up to maximum 42 months)
- RP2D Phase: Number of Participants With Dose Modifications of GSK3326595(Up to maximum 42 months)
- RP2D Phase: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters(Baseline (Day 1) and up to maximum 42 months)
- RP2D Phase: Number of Participants With Worst Case Change From Baseline in Hematology Parameters(Baseline (Day 1) and up to maximum 42 months)
- RP2D Phase: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters(Baseline (Day 1) and up to maximum 42 months)
- RP2D Phase: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters(Baseline (Day 1) and up to maximum 42 months)
- RP2D Phase: Changes From Baseline in Urine Potential of Hydrogen (pH)(Baseline (Day 1) and up to Week 184)
- RP2D Phase: Changes From Baseline in Urine Specific Gravity(Baseline (Day 1) and up to Week 184)
- RP2D Phase: Number of Participants With Worst-case Increase Post-baseline Relative to Baseline in Vital Signs(Baseline (Day 1) and up to maximum 42 months)