A Phase I First Time in Human Open Label Study of GSK3745417 Administered With and Without Anticancer Agents in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 97
- 试验地点
- 12
- 主要终点
- Part 1A: Number of Participants Achieving Dose-limiting Toxicity (DLT) Following Administration of GSK3745417 Alone (Q1W)
研究概览
简要总结
This study aims to evaluate the safety, tolerability, and preliminary clinical activity and establish a recommended dose of GSK3745417 administered alone (Part 1A) or co-administered (Part 2A) with dostarlimab in participants with refractory/relapsed solid tumors. Both parts will consist of a dose escalation phase.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This will be 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
- •Participant must be more than or equal to (>=)18 years of age.
- •Participants with advanced/recurrent solid tumors, who have progressed on, be intolerant of, or ineligible for, all available therapies for which clinical benefit has been established.
- •Histological or cytological documentation of an advanced solid tumor.
- •Participants must provide a fresh biopsy.
- •Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-
- •Adequate organ function per protocol specifications.
- •Male or female participants.
- •Female participants are eligible to participate if they are not breastfeeding or pregnant (or intend to breastfeed or become pregnant). Women of childbearing potential must use a highly effective method of contraception.
- •Capable of giving signed informed consent.
排除标准
- •Active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years.
- •Concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment.
- •Current unstable liver or biliary disease.
- •History of vasculitis at any time prior to study treatment.
- •Evidence or history of significant active bleeding or coagulation disorder.
- •Active infection requiring systemic treatment, known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen or hepatitis C.
- •QT duration corrected for heart rate by Fridericia's formula (QTcF) more than (>)450 milliseconds (msec) or QTcF >480 msec for participants with bundle branch block.
- •Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
- •Recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
- •History or evidence of cardiovascular (CV) risk
- •Recent (within the past 6 months) history of symptomatic pericarditis.
- •History of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing pneumonia, or evidence of active, non-infectious pneumonitis.
- •History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- •Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions.
- •Prior treatment with the following agents:
- •Stimulator of Interferon Genes (STING) agonist at any time.
- •Anticancer therapy or investigational therapy or used an investigational device within 28 days or 5 half-lives of the drug, whichever is shorter.
- •Checkpoint inhibitors, including Programmed death receptor-1 (PD-1), Programmed death Ligand-1 (PD-L1), PD-L2 and Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors within 28 days.
- •Prior radiation therapy: permissible if at least 1 non-irradiated measurable lesion is available for assessment according to RECIST version 1.1 or if a solitary measurable lesion was irradiated, objective progression is documented.
- •Pregnant and/or breast feeding participants or those who plan to become pregnant and/or breastfeed.
- •Receipt of any live vaccine within 30 days of the start of study treatment.
- •Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
- •Major surgery less than or equal to (<=)28 days before the first dose of study treatment. Participants must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study treatment.
- •Participants with signs/symptoms suggestive of Coronavirus Disease-2019 (COVID-19) within 14 days of study entry, or with known exposure to COVID-19 within 14 days prior to study entry.
- •Participants are excluded from Part 2A of the study if they have known hypersensitivity to dostarlimab or associated excipients.
研究组 & 干预措施
Part 2A: Participants receiving GSK3745417 + dostarlimab, Dose escalation Cohort
干预措施: GSK3745417 (Drug)
Part 1A: Participants receiving GSK3745417, Dose-escalation Cohort
干预措施: GSK3745417 (Drug)
Part 2A: Participants receiving GSK3745417 + dostarlimab, Dose escalation Cohort
干预措施: Dostarlimab (Drug)
结局指标
主要结局
Part 1A: Number of Participants Achieving Dose-limiting Toxicity (DLT) Following Administration of GSK3745417 Alone (Q1W)
时间窗: Up to 21 Days
AE is DLT if deemed clinically relevant,attributed to study intervention \& met DLT criteria:CytokineReleaseSyndrome (CRS) (Grade(G) 3/4);Liver Toxicity: ALT≥3xULN + bilirubin≥2xULN/INR\>1.5, ALT≥5x ULN+≥2x baseline with liver,metastases/tumor infiltration or HCC;G≥3 non-hematologic exceptions: Transient lab abnormalities, CRS≤G2,Controlled diarrhea,Resolving nausea/vomiting,Alopecia,G3 fatigue\<7 days,G3 headache resolving in 24 hrs;G≥3 immune-related toxicity unresolved in 8 days despite therapy and G≥3 infusion reactions included;Other toxicities: G≥2 uveitis, Unresolved eye pain/blurred vision in 2 wks,Endocrine toxicity needing hormone replacement,Colitis/diarrhea unresolved for ≥7Days despite steroids,ICANS;Hematologic toxicity includes: Neutropenia(G4 ≥7Days or G3/4 with infection/febrile neutropenia),Thrombocytopenia (G4/G3 with bleeding/transfusion),Anemia (G4/G3 needing transfusion);Other events deemed DLTs by the investigator and GSK Medical Monitor per NCI-CTCAE v5.0
Parts 1A: Number of Participants Achieving DLT Following Administration of GSK3745417 Alone (Q3W)
时间窗: Up to 29 Days
AE is DLT if deemed clinically relevant,attributed to study intervention \& met DLT criteria:CytokineReleaseSyndrome (CRS) (Grade(G) 3/4);Liver Toxicity: ALT≥3xULN + bilirubin≥2xULN/INR\>1.5, ALT≥5x ULN+≥2x baseline with liver,metastases/tumor infiltration or HCC;G≥3 non-hematologic exceptions: Transient lab abnormalities, CRS≤G2,Controlled diarrhea,Resolving nausea/vomiting,Alopecia,G3 fatigue\<7 days,G3 headache resolving in 24 hrs;G≥3 immune-related toxicity unresolved in 8 days despite therapy and G≥3 infusion reactions included;Other toxicities: G≥2 uveitis, Unresolved eye pain/blurred vision in 2 wks,Endocrine toxicity needing hormone replacement,Colitis/diarrhea unresolved for ≥7Days despite steroids,ICANS;Hematologic toxicity includes: Neutropenia(G4 ≥7Days or G3/4 with infection/febrile neutropenia),Thrombocytopenia (G4/G3 with bleeding/transfusion),Anemia (G4/G3 needing transfusion);Other events deemed DLTs by the investigator and GSK Medical Monitor per NCI-CTCAE v5.0
Parts 2A: Number of Participants Achieving DLT Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)
时间窗: Up to 29 Days
AE is DLT if deemed clinically relevant,attributed to study intervention \& met DLT criteria:CytokineReleaseSyndrome (CRS) (Grade(G) 3/4);Liver Toxicity: ALT≥3xULN + bilirubin≥2xULN/INR\>1.5, ALT≥5x ULN+≥2x baseline with liver,metastases/tumor infiltration or HCC;G≥3 non-hematologic exceptions: Transient lab abnormalities, CRS≤G2,Controlled diarrhea,Resolving nausea/vomiting,Alopecia,G3 fatigue\<7 days,G3 headache resolving in 24 hrs;G≥3 immune-related toxicity unresolved in 8 days despite therapy and G≥3 infusion reactions included;Other toxicities: G≥2 uveitis, Unresolved eye pain/blurred vision in 2 wks,Endocrine toxicity needing hormone replacement,Colitis/diarrhea unresolved for ≥7Days despite steroids,ICANS;Hematologic toxicity includes: Neutropenia(G4 ≥7Days or G3/4 with infection/febrile neutropenia),Thrombocytopenia (G4/G3 with bleeding/transfusion),Anemia (G4/G3 needing transfusion);Other events deemed DLTs by the investigator and GSK Medical Monitor per NCI-CTCAE v5.0
Parts 2A: Number of Participants Achieving Dose-limiting Toxicity (DLT) Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)
时间窗: Up to 29 Days
AE is DLT if deemed clinically relevant,attributed to study intervention \& met DLT criteria:CytokineReleaseSyndrome (CRS) (Grade(G) 3/4);Liver Toxicity: ALT≥3xULN + bilirubin≥2xULN/INR\>1.5, ALT≥5x ULN+≥2x baseline with liver,metastases/tumor infiltration or HCC;G≥3 non-hematologic exceptions: Transient lab abnormalities, CRS≤G2,Controlled diarrhea,Resolving nausea/vomiting,Alopecia,G3 fatigue\<7 days,G3 headache resolving in 24 hrs;G≥3 immune-related toxicity unresolved in 8 days despite therapy and G≥3 infusion reactions included;Other toxicities: G≥2 uveitis, Unresolved eye pain/blurred vision in 2 wks,Endocrine toxicity needing hormone replacement,Colitis/diarrhea unresolved for ≥7Days despite steroids,ICANS;Hematologic toxicity includes: Neutropenia(G4 ≥7Days or G3/4 with infection/febrile neutropenia),Thrombocytopenia (G4/G3 with bleeding/transfusion),Anemia (G4/G3 needing transfusion);Other events deemed DLTs by the investigator and GSK Medical Monitor per NCI-CTCAE v5.0
Parts 1A: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (STEAEs) by Severity
时间窗: Up to approximately 62 weeks
AE is any untoward medical occurrence in clinical investigation participant, temporally associated with the use of medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is 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. TEAE is an event that emerges during treatment having been absent pretreatment or worsens relative to the pretreatment state. AEs were graded by the investigator according to National Cancer Institute Common Terminology Criteria for AE (NCI-CTCAE) (version 5.0):G1=Mild,G2=Moderate,G3=Severe or medically significant but not immediately life-threatening,G4=Life-threatening consequences,G5=Death related AE.
Parts 2A: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (STEAEs) by Severity
时间窗: Up to approximately 93 weeks
AE is any untoward medical occurrence in clinical investigation participant, temporally associated with the use of medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is 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. TEAE is an event that emerges during treatment having been absent pretreatment or worsens relative to the pretreatment state. AEs were graded by the investigator according to NCI-CTCAE v5.0: G1=Mild, G2=Moderate, G3=Severe or medically significant but not immediately life-threatening, G4=Life-threatening consequences, G5=Death related AE.
Crossover Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (STEAEs) by Severity
时间窗: Up to 30.3 weeks
AE is any untoward medical occurrence in clinical investigation participant, temporally associated with the use of medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is 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. TEAE is an event that emerges during treatment having been absent pretreatment or worsens relative to the pretreatment state. AEs were graded by the investigator according to NCI-CTCAE v5.0: G1=Mild, G2=Moderate, G3=Severe or medically significant but not immediately life-threatening, G4=Life-threatening consequences, G5=Death related AE.
次要结局
- Part 1A: Maximum Observed Concentration (Cmax) Following Administration of GSK3745417 Alone (Q1W)(Week 1 to 6, 9, 10, 12, 19)
- Part 1A: Area Under the Concentration-time Curve (AUC0-tau) Following Administration of GSK3745417 Alone (Q1W)(Week 1 to 6, 9, 10, 12, 19)
- Part 1A: GSK3745417 Concentrations in Plasma Following Administration of GSK3745417 Alone (Q1W)(Pre-dose on weeks(W) 1-6,9,10,12,19,55;end of infusion(EOI)+5minute(min) on W 1-6, 9,10,12,19,55;EOI+4 hour(HR)/8 HR on W 1-6, 9, 10, 12, 19;EOI+15min/30min/45min/1HR on W 1-6, 9,12;EOI+24HR on W 1-6, 9,10,12; EOI+2HR on W 1-6,9,10,12,19,55)
- Part 1A: Apparent Terminal Phase Half-life (t1/2) Following Administration of GSK3745417 Alone (Q1W)(Week 1 to 6, 9, 10, 12, 19)
- Part 1A: GSK3745417 Concentrations in Plasma Following Administration of GSK3745417 Alone (Q3W)(Pre-dose on W 1, 4, 7, 10, 13, 16, 19; EOI+5min/ 15min/ 30 min/ 45 min/1HR/ 2HR/ 4HR on W 1, 4, 7, 10, 13, 16, 19; EOI+8HR/ 24HR on W 1, 4, 7, 10, 13, 16)
- Part 1A: AUC(0-tau) Following Administration of GSK3745417 Alone (Q3W)(Week 1, 4, 7, 10, 13, 16, 19)
- Part 1A: Cmax Following Administration of GSK3745417 Alone (Q3W)(Week 1, 4, 7, 10, 13, 16, 19)
- Part 1A: T1/2 Following Administration of GSK3745417 Alone (Q3W)(Week 1, 4, 7, 10, 13, 16, 19)
- Part 2A: GSK3745417 Concentrations in Plasma Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)(Pre-dose,EOI+5min/2HR/4HR on W 1 to 5, 7, 10, 13, 19, 37, 55; EOI+15min/ 30min/ 45 min/ 1HR on W 1, 4, 7; EOI+8HR on W 1 to 5, 7, 10, 13, 19; EOI+24HR on W 1 to 5, 7, 10)
- Part 2A: AUC(0-tau) Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)(Week 1 to 5, 7, 10, 13, 19)
- Part 2A: Cmax Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)(Week 1 to 5, 7, 10, 13, 19)
- Part 2A: T1/2 Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)(Week 1 to 5, 7, 10, 13, 19)
- Part 2A: GSK3745417 Concentrations in Plasma Following Administration of GSK3745417 in Combination With Dostarlimab (Imaging Q1W)(Pre-dose and EOI+5min/ 2HR/ 4HR on W 1, 2, 5, 6, 8, 11, 14, 20, 38; EOI+15min/ 30min/ 45min/ 1HR/ 6HR on W 1 and 8; EOI+8HR in W 1, 2, 5, 6, 8; EOI+24HR on W 1, 2, 5, 8.)
- Part 2A: AUC(0-tau) Following Administration of GSK3745417 in Combination With Dostarlimab (Imaging Q1W)(Week 1, 2, 5, 6, 8)
- Part 2A: Cmax Following Administration of GSK3745417 in Combination With Dostarlimab (Imaging Q1W)(Week 1, 2, 5, 6, 8)
- Part 2A: T1/2 Following Administration of GSK3745417 in Combination With Dostarlimab (Imaging Q1W)(Week 1, 2, 5, 6, 8)
- Part 2A: GSK3745417 Concentrations in Plasma Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)(Pre-dose on W 1, 4, 7, 10, 13, 19, 37, 55, 73, 91; EOI+5min/ 4HR on W 1, 4, 7, 10, 13, 19, 37, 55, 91; EOI+15min/ 30min/ 45min/ 1HR/ 6HR on W 1, 4, 7; EOI+2HR on W 1, 4, 7, 10, 13, 19, 37, 55, 73; EOI+8HR/24 HR on W 1, 4, 7, 10, 13, 19, 91)
- Part 2A: AUC(0-tau) Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)(Week 1, 4, 7, 10, 13, 19, 91)
- Part 2A: Cmax Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)(Week 1, 4, 7, 10, 13, 19, 91)
- Part 2A: T1/2 Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)(Week 1, 4, 7, 10, 13, 19, 91)
- Crossover Phase: AUC(0-tau) Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)(Crossover Week 1, 4, 7, 10, 13, 19)
- Crossover Phase: GSK3745417 Concentrations in Plasma Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)(Pre-dose and EOI+5min/2HR/ 4HR/ 8HR on crossover W 1, 4, 7, 10, 13, 19; EOI+12HR/18HR on crossover W 4; EOI+15min/ 30 min/45 min/1HR/6HR/24HR on crossover W 1, 4, 7)
- Crossover Phase: Cmax Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)(Crossover Week 1, 4, 7, 10, 13, 19)
- Crossover Phase: T1/2 Following Administration of GSK3745417 in Combination With Dostarlimab (Q3W)(Crossover Week 1, 4, 7, 10, 13, 19)
- Crossover Phase: GSK3745417 Concentrations in Plasma Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)(Pre-dose and EOI+5min/ 2HR/4HR on crossover W 1-4, 7,10,19; EOI+15min/30 min/45 min/1HR/ 6HR/ 24HR on crossover W 1,4,7;EOI+12HR/18HR on crossover W 4;EOI+8HR on crossover W 1-4,7,10)
- Crossover Phase: AUC(0-tau) Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)(Crossover Week 1, 2, 3, 4, 5, 7, 10)
- Crossover Phase: Cmax Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)(Crossover Week 1, 2, 3, 4, 5, 7, 10)
- Crossover Phase: T1/2 Following Administration of GSK3745417 in Combination With Dostarlimab (Q1W)(Crossover Week 1, 2, 3, 4, 5, 7, 10)