An Open-label, Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of MEDI9253, a Recombinant Newcastle Disease Virus Encoding Interleukin-12, in Combination With Durvalumab in Participants With Select Advanced/Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- AstraZeneca
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
研究概览
简要总结
Study D7880C00001 is a first-in-human (FIH), Phase 1, open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of MEDI9253 in combination with durvalumab in adult participants with select advanced/metastatic solid tumors.
详细描述
Up to approximately 192 participants may be assigned to study intervention in the study across approximately 30 sites globally.
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
入排标准
- 年龄范围
- 18 Years 至 101 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must be at least 18 years old at signing of informed consent.
- •Body weight > 35 kg at screening.
排除标准
- •1 Primary central nervous system (CNS) disease is excluded, as well as untreated or uncontrolled metastatic CNS involvement, leptomeningeal disease, or cord compression.
- •NOTE: CNS disease that has been treated and stable/controlled for at least 3 months is permitted. Participants with CNS disease controlled via systemic steroids are not permitted.
研究组 & 干预措施
MEDI9253 Single Dose Level 1 + Durvalumab 1500 mg Q4W
Participants will receive intravenous (IV) infusion of a single dose of MEDI9253 dose level 1 on Day 1. After 14 days (+7 days) of MEDI9253 dose, participants will receive IV durvalumab at 1500 mg once every 4 weeks (Q4W) until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: MEDI9253 (Biological)
MEDI9253 Single Dose Level 1 + Durvalumab 1500 mg Q4W
Participants will receive intravenous (IV) infusion of a single dose of MEDI9253 dose level 1 on Day 1. After 14 days (+7 days) of MEDI9253 dose, participants will receive IV durvalumab at 1500 mg once every 4 weeks (Q4W) until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: Durvalumab (Biological)
MEDI9253 Single Dose Level 2 + Durvalumab 1500 mg Q4W
Participants will receive IV infusion of a single dose of MEDI9253 dose level 2 on Day 1. After 14 days (+7 days) of MEDI9253 dose, participants will receive IV durvalumab at 1500 mg Q4W until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: MEDI9253 (Biological)
MEDI9253 Single Dose Level 2 + Durvalumab 1500 mg Q4W
Participants will receive IV infusion of a single dose of MEDI9253 dose level 2 on Day 1. After 14 days (+7 days) of MEDI9253 dose, participants will receive IV durvalumab at 1500 mg Q4W until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: Durvalumab (Biological)
MEDI9253 Multiple Dose Level 2 + Durvalumab 1500 mg Q4W
Participants will receive IV infusion of 3 weekly doses (±2 days) of MEDI9253 dose level 2 over a maximum of 17 days, with a minimum of 5 days between each dose. After 14 days (+7 days) post the last dose of MEDI9253, participants will receive IV durvalumab at 1500 mg Q4W until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: MEDI9253 (Biological)
MEDI9253 Multiple Dose Level 2 + Durvalumab 1500 mg Q4W
Participants will receive IV infusion of 3 weekly doses (±2 days) of MEDI9253 dose level 2 over a maximum of 17 days, with a minimum of 5 days between each dose. After 14 days (+7 days) post the last dose of MEDI9253, participants will receive IV durvalumab at 1500 mg Q4W until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: Durvalumab (Biological)
MEDI9253 Multiple Dose Level 3 + Durvalumab 1500 mg Q4W
Participants will receive IV infusion of 3 weekly doses (±2 days) of MEDI9253 dose level 3 over a maximum of 17 days, with a minimum of 5 days between each dose. After 14 days (+7 days) post the last dose of MEDI9253, participants will receive IV durvalumab at 1500 mg Q4W until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: MEDI9253 (Biological)
MEDI9253 Multiple Dose Level 3 + Durvalumab 1500 mg Q4W
Participants will receive IV infusion of 3 weekly doses (±2 days) of MEDI9253 dose level 3 over a maximum of 17 days, with a minimum of 5 days between each dose. After 14 days (+7 days) post the last dose of MEDI9253, participants will receive IV durvalumab at 1500 mg Q4W until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: Durvalumab (Biological)
MEDI9253 Multiple Dose Level 3+Durva 1500 mg Q4W Seq 3A-DESENS
Participants will receive IV infusion of 3 weekly doses (±2 days) of MEDI9253 dose level 3 over a maximum of 17 days, with a minimum of 5 days between each dose (first dose was administered at dose level 2 while second and third doses were administered at dose level 3). After 14 days (+7 days) post the last dose of MEDI9253, participants will receive IV durvalumab at 1500 mg Q4W until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: MEDI9253 (Biological)
MEDI9253 Multiple Dose Level 3+Durva 1500 mg Q4W Seq 3A-DESENS
Participants will receive IV infusion of 3 weekly doses (±2 days) of MEDI9253 dose level 3 over a maximum of 17 days, with a minimum of 5 days between each dose (first dose was administered at dose level 2 while second and third doses were administered at dose level 3). After 14 days (+7 days) post the last dose of MEDI9253, participants will receive IV durvalumab at 1500 mg Q4W until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: Durvalumab (Biological)
MEDI9253 Multiple Dose Level 3+Durva 1500 mg Q4W Conc3B-DESENS
Participants will receive IV infusion of 3 weekly doses (±2 days) of MEDI9253 dose level 3 over a maximum of 17 days, with a minimum of 5 days between each dose (first dose was administered at dose level 2 while second and third doses were administered at dose level 3) along with IV infusion of durvalumab 1500 mg Q4W starting from Day 8 (on the same day of second dose of MEDI9253) until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: MEDI9253 (Biological)
MEDI9253 Multiple Dose Level 3+Durva 1500 mg Q4W Conc3B-DESENS
Participants will receive IV infusion of 3 weekly doses (±2 days) of MEDI9253 dose level 3 over a maximum of 17 days, with a minimum of 5 days between each dose (first dose was administered at dose level 2 while second and third doses were administered at dose level 3) along with IV infusion of durvalumab 1500 mg Q4W starting from Day 8 (on the same day of second dose of MEDI9253) until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity, for up to 2 years.
干预措施: Durvalumab (Biological)
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
时间窗: Day 1 through 76.14 weeks (maximum observed duration)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization, persistent or significant disability/incapacity, important medical event, congenital anomaly/birth defect (in the offspring of the subject). The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Dose-limiting Toxicities (DLTs)
时间窗: From the first dose of MEDI9253 through Day 14 (single dose cohorts) or Day 28 (multiple dose cohorts)
DLT: Any study drug-related Grade (G) 3 or higher toxicity; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) together with total bilirubin (TBL) ≥ 2 × ULN; Grade ≥ 2 myocarditis; Grade 2 non-infectious pneumonitis that does not resolve to ≤ G 1 within 7 days; any ≥ G 2 MEDI9253-related toxicity that prevents the administration of more than 1 dose of MEDI9253; in the sequential dosing cohorts, any ≥ Grade 2 MEDI9253-related toxicity that prevents administration of the first dose of durvalumab; any AE that after consultation with the sponsor and investigators, is deemed to be a DLT.
Number of Participants With TEAEs Leading to Discontinuation
时间窗: Day 1 through 76.14 weeks (maximum observed duration)
Participants were permanently discontinued (PED) due to TEAE if: an AE that in the opinion of the investigator or the sponsor, warrants discontinuation of further dosing; an AE that met the criteria for a DLT during the DLT-evaluation period (from the first dose of MEDI9253 through Day 14 \[single dose cohorts\] or Day 28 \[multiple dose cohorts\]) unless criteria for initiation of durvalumab are met; an AE that required permanent discontinuation of study drug per toxicity management guidelines.
Number of Participants With Abnormal Vital Signs Reported as TEAEs
时间窗: Day 1 through 76.14 weeks (maximum observed duration)
Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (body temperature, blood pressure, pulse oximetry \[on MEDI9253 dosing days only\], pulse rate, and respiratory rate).
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
时间窗: Day 1 through 76.14 weeks (maximum observed duration)
Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of hematology, clinical chemistry, coagulation, and urinalysis.
Number of Participants With Abnormal Electrocardiogram (ECG) Parameters Reported as TEAEs
时间窗: Day 1 through 76.14 weeks (maximum observed duration)
Number of participants with abnormal ECG reported as TEAEs are reported.
Number of Participants With Abnormal Physical Examination Reported as TEAEs
时间窗: Day 1 through 76.14 weeks (maximum observed duration)
Number of participants with abnormal physical examination reported as TEAEs are reported.
次要结局
- Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)(Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks))
- Time to Response (TTR) According to RECIST V1.1(Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks))
- Percentage of Participants With Disease Control Rate (DCR) at 16 Weeks According to RECIST v1.1(Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks))
- Progression Free Survival (PFS) According to RECIST v1.1(Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks))
- Overall Survival (OS)(Baseline (Days -28 to -1) through 90 days post last dose (76.14 weeks))
- Whole Blood Viral Genome Concentrations of MEDI9253 for Single Dose Cohorts(Pre-dose, end of infusion (EOI); 1, 2, 4, 6, 9, 12, 24, 32, 40, 48, 72 hours and Days 7, 14, 21, 42 post EOI in Cycle 1 (each cycle is 28 days); and Durvalumab Cycle 3 pre-dose)
- Whole Blood Viral Genome Concentrations of MEDI9253 for Multiple Dose Cohorts(Pre-dose, end of infusion, 1 day post dose on Days 1, 8, and 15; and 7 days post Dose 3; Durvalumab Cycle 1 (each cycle is 28 days)-Days 29, 36; Cycle 2-Days 36, 57; Cycle 3 Pre-dose Days 64, 85)
- Plasma Interleukin (IL)-12 Concentrations for Single Dose Cohorts(Pre-dose, 1, 2, 4, 6, 9, 12, 24, 32, 40, 48, 72 hours and Days 7, 14, 21, 42 post end of infusion, and Durvalumab Cycle 3 (each cycle is 28 days) pre-dose)
- Plasma IL-12 Concentrations for Multiple Dose Cohorts(Pre-dose, end of infusion, 1 day post dose on Days 1, 8, and 15; and 7 days post Dose 3; Durvalumab Cycle 1 (each cycle is 28 days)-Days 29, 36; Cycle 2-Days 36, 57; Cycle 3 Pre-dose Days 64, 85)
- Cluster of differentiation (CD) 8 T cell Density as Assessed by Immunohistochemistry (IHC)(Baseline (Day -28 to -Day 1) and on Days 8, 15, 36, and 57)
- Percentage of Programmed Cell Death Ligand 1 (PD-L1) Positive Tumor Cells by IHC(Baseline (Day -28 to -Day 1) and on Days 8, 15, 36, and 57)
- Percentage of Combined Tumor and Immune PD-L1 Positive Tumor Cells in Tumor Areas as Assessed by IHC(Baseline (Day -28 to -Day 1) and on Days 8, 15, 36, and 57)
- Number of Participants with Positive Neutralizing Antibody (nAb) Response to MEDI9253(Baseline (pre-dose Day 1), Cycle 1 (each cycle is 28 days) Day 22, Cycle 2 Day 1, Cycle 3 Day 1, and 28 days after the last dose (7.47 weeks))