A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to Evaluate Novel Combination Therapies in Subjects With Previously Treated Advanced EGFRm NSCLC
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 43
- 试验地点
- 13
- 主要终点
- Number of Participants With Dose-limiting Toxicities (DLTs) in Part 1
研究概览
简要总结
The objective of this study is to investigate the safety, tolerability, and antitumor activity of novel combination therapies administered in participants with advanced EGFRm NSCLC.
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
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Weight ≥ 35 kg
- •Diagnosed with histologically or cytologically confirmed locally advanced/metastatic NSCLC with EGFRm
- •For Arm A (Oleclumab + Osimertinib arms): must have received 1 prior line of therapy with an EGFR tyrosine kinase inhibitor (TKI) and confirmed T790M negative
- •For Arm B (Oleclumab + AZD4635 arms): must have received at least 2 but not more than 4 prior lines of therapy.
排除标准
- •Receipt of an EGFR TKI within 14 days of the first dose of study treatment
- •Receipt of any conventional or investigational anticancer therapy not otherwise specified within 21 days of the planned first dose
- •Prior receipt of any investigational immunotherapy. Participants may have received agents that have local health authority approval for the disease indication
- •Concurrent enrollment in another therapeutic clinical study. Enrollment in observational studies will be allowed.
- •Participants with a history of venous thrombosis within the past 3 months
- •Participants with prior history of myocardial infarction, transient ischemic attack, or stroke in the last 6 months
- •Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment
- •Other invasive malignancy within 2 years
- •Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression
- •Current or prior use of immunosuppressive medication within 14 days prior to the first dose
- •Additional Exclusion Criteria for Arm A
- •Concurrent treatment (or inability to stop therapy) with medications or herbal supplements known to be potent inducers of cytochrome P (CYP) 3A4
- •Participants has a history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD
- •Participants requires continuous supplemental oxygen for any reason
- •Additional Exclusion Criteria for Arm B
- •Herbal preparations/medications are not allowed throughout the study
- •History of seizures excluding those that occurred due to previously untreated CNS metastasis
研究组 & 干预措施
Oleclumab Dose 2 + Osimertinib Dose 1
In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD. In Part 2 (dose-expansion), participants (including participants dosed at the RP2D in Part 1) will receive IV oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD until documentation of disease progression, intolerable toxicity, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Biological)
Oleclumab Dose 1 + Osimertinib Dose 1
In Part 1 (dose-escalation), participants will receive intravenous oleclumab (MEDI9447) Dose 1 every 2 weeks (Q2W) and oral osimertinib Dose 1 once daily (QD).
干预措施: Osimertinib (Drug)
Oleclumab Dose 2 + Osimertinib Dose 1
In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD. In Part 2 (dose-expansion), participants (including participants dosed at the RP2D in Part 1) will receive IV oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD until documentation of disease progression, intolerable toxicity, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Osimertinib (Drug)
Oleclumab Dose 1 + AZD4635 Dose 1
In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 1 QD.
干预措施: AZD4635 (Drug)
Oleclumab Dose 2 + AZD4635 Dose 2
In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral AZD4635 Dose 2 QD.
干预措施: Oleclumab (Biological)
Oleclumab Dose 2 + AZD4635 Dose 2
In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral AZD4635 Dose 2 QD.
干预措施: AZD4635 (Drug)
Oleclumab Dose 1 + AZD4635 Dose 2
In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 2 QD.
干预措施: AZD4635 (Drug)
Oleclumab Dose 1 + AZD4635 Dose 2
In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 2 QD.
干预措施: Oleclumab (Biological)
Oleclumab Dose 1 + Osimertinib Dose 1
In Part 1 (dose-escalation), participants will receive intravenous oleclumab (MEDI9447) Dose 1 every 2 weeks (Q2W) and oral osimertinib Dose 1 once daily (QD).
干预措施: Oleclumab (Biological)
Oleclumab Dose 1 + AZD4635 Dose 1
In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 1 QD.
干预措施: Oleclumab (Biological)
结局指标
主要结局
Number of Participants With Dose-limiting Toxicities (DLTs) in Part 1
时间窗: From Day 1 to Day 28 after first dose of study drug
A DLT was defined as \>= Grade 3 toxicity or adverse events (AE) occurred during DLT evaluation period which included any Grade 4 immune-mediated (immune nature) AE, anemia, thrombocytopenia (present \> 4 days), or neutropenia (present \> 4 days); \>= Grade 3 colitis or pneumonitis or interstitial lung disease (ILD); \>= Grade 3 nausea, vomiting, or diarrhea (not resolved to \<= Grade 2 in 3 days); Grade 2 pneumonitis or ILD (not resolved to \<= Grade 1 in 3 days); Grade 3 thrombocytopenia with bleeding, any grade febrile neutropenia; convulsions, seizures, or stroke; protocol defined elevations of isolated liver transaminase, isolated total bilirubin (TBL), or Hy's Law; confirmed QT interval corrected for heart rate by Fridericia's formula prolongation (\>= 501 msec) on triplicate electrocardiograms within a short period of time; or any other toxicity greater than that at baseline, was clinically significant and/or unacceptable, and was judged to be a DLT by the Dose Escalation Committee.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Parts 1 and 2
时间窗: From Day 1 through 90 days of the last dose of study drug (approximately 37 months)
An 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; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. 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 Abnormal Vital Signs and Physical Examination Reported as TEAEs in Parts 1 and 2
时间窗: From Day 1 through 90 days of the last dose of study drug (approximately 37 months)
Participants with abnormal vital signs (heart rate, blood pressure, temperature, and respiratory rate) and physical examination reported as TEAEs are reported.
Number of Participants With Notable QTc Interval in Parts 1 and 2
时间窗: From Day 1 through 90 days of the last dose of study drug (approximately 37 months)
Notable QTc intervals included single beat changes from baseline (Day 1) values (\> 30, \> 60, and \> 90 milliseconds). Participants who had notable QTc interval are reported.
Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 in Part 2
时间窗: From Day 1 through 90 days of the last dose of study drug (approximately 37 months)
The OR is defined as confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between.
Number of Participants With Abnormal Laboratory Parameters Reported as TEAEs in Parts 1 and 2
时间窗: From Day 1 through 90 days of the last dose of study drug (approximately 37 months)
Participants with abnormal laboratory parameters reported as TEAEs are reported. Laboratory analysis included hematology, clinical chemistry, thyroid function tests, and urinalysis.
次要结局
- Duration of Response (DoR) Per RECIST v 1.1 for Parts 1 and 2(From Day 1 through 90 days of the last dose of study drug (approximately 37 months))
- Percentage of Participants With Disease Control (DC) in Parts 1 and 2(From Day 1 through 90 days of the last dose of study drug (approximately 37 months))
- Progression Free Survival (PFS) for Parts 1 and 2(From Day 1 through 90 days of the last dose of study drug (approximately 37 months))
- Overall Survival (OS) for Parts 1 and 2(From Day 1 through 90 days of the last dose of study drug (approximately 37 months))
- Percentage of Participants With OR by T790M Status at Baseline (Determined by a Central Laboratory) for Parts 1 and 2(From Baseline (Days -28 to -1) through 90 days of the last dose of study drug (approximately 37 months))
- Percentage of Participants With DC by T790M Status at Baseline (Determined by a Central Laboratory) for Parts 1 and 2(From Baseline (Days -28 to -1) through 90 days of the last dose of study drug (approximately 37 months))
- Observed Serum Concentration at the Time of End of Infusion (CEOI) of Oleclumab (MEDI9447) Over Time(Predose (within 90 minutes prior to start of infusion) and postdose (10 minutes after the end of infusion) on Days 1 and 57)
- Observed Lowest Serum Concentration (Ctrough) of MEDI9447 Over Time(Predose (within 90 minutes prior to start of infusion) on Day 57)
- Maximum Plasma Concentration (Cmax) of Osimertinib and Its Metabolite (AZ5104)(Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, and 4 hours) on Days 1 and 29)
- Cmax of AZD4635 and Its Metabolites (SSP-005173X and SSP-005174X)(Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57)
- Tmax of AZD4635 and Its Metabolites (SSP-005173X and SSP-005174X)(Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57)
- Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of AZD4635 and Its Metabolites (SSP-005173X and SSP-005174X)(Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57)
- Number of Participants With Positive Post-baseline for Anti-oleclumab Antibodies(Predose on Days 1 (Baseline), 29, and 57, and later every 12 weeks through the 12 months and 90 days after the last dose of study drug (approximately 37 months))