A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab With Stereotactic Body Radiation Therapy (SBRT) for the Treatment of Patients With Unresected Stage I/II, Lymph-node Negative Non-small Cell Lung Cancer (PACIFIC-4/RTOG-3515) Osimertinib Following SBRT, a Single Arm Cohort for Patients With Unresected Stage I/II, Lymph Node Negative NSCLC Harboring a Sensitizing EGFR Mutation
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 724
- 试验地点
- 209
- 主要终点
- Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 in subpopulation of patients with Stage I/II NSCLC
研究概览
简要总结
This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study assessing the efficacy and safety of durvalumab with SoC SBRT versus placebo with SoC SBRT in patients with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC.
An additional cohort will assess Osimertinib following SBRT in patients with early stage unresected T1 to T3N0M0 NSCLC harbouring an EGFR mutation.
详细描述
Patients with Stage I/II lymph node negative NSCLC and confirmed to meet all eligibility criteria will be randomized 1:1 to receive either Durvalumab + SoC SBRT or placebo + SoC SBRT.
The primary objective of main cohort is to assess the efficacy of Durvalumab with SoC SBRT compared to placebo with SoC SBRT in terms of PFS. Key secondary is to assess the efficacy of Durvalumab with SoC SBRT compared to placebo with SoC SBRT in terms of Overall Survival (OS).
In addition, a study cohort with a sufficient number of patients harboring an EGFR-TKI sensitizing mutation, will receive Osimertinib treatment after completion of SoC SBRT as definitive treatment of Stage I/II lymph node-negative NSCLC. The primary objective of Osimertinib cohort is to assess efficacy of Osimertinib following SoC SBRT in terms of 4-year PFS. Key secondary objectives include safety, OS and efficacy of Osimertininb treatment with SBRT.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double- Blind
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Main Cohort Key Inclusion Criteria:
- •Age ≥18 years
- •Planned SoC SBRT as definitive treatment
- •World Health Organization (WHO)/ECOG PS of 0, 1 or 2
- •Life expectancy of at least 12 weeks
- •Body weight >30 kg
- •Submission of tumor tissue sample if available
- •Adequate organ and marrow function required
- •Patients with central or peripheral lesions are eligible
- •Staging studies must be done during screening (PET-CT within 10 weeks)
- •Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions
- •Main Cohort Key
排除标准
- •Mixed small cell and non-small cell cancer
- •History of allogeneic organ transplantation
- •History of another primary malignancy with exceptions
- •History of active primary immunodeficiency
- •Epidermal growth factor receptor local testing is strongly recommended prior to enrollment. Patients with a tumor harboring an EGFRm per local testing will be excluded from the main cohort
- •Prior exposure to immune-mediated therapy with exceptions
- •Osimertinib Cohort Key Inclusion Criteria
- •Age ≥18 years
- •Planned SoC SBRT as definitive treatment
- •WHO/ECOG PS of 0, 1, or 2
- •Patients with central or peripheral lesions are eligible
- •Patients with a history of metachronous NSCLC and synchronous lesions are eligible with some exceptions
- •Staging studies must be done during screening (PET-CT within 10 weeks)
- •Submission of tumor tissue sample if available
- •Confirmation by local laboratory that the tumor harbors one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R)
- •Adequate bone marrow reserve or organ function required
- •Female patients should be using highly effective contraceptive measures
- •Male patients should be asked to use barrier contraceptives (ie, condoms) during sex with all partners during the trial and avoid procreation
- •Osimertinib Cohort Key Exclusion Criteria
- •Mixed small cell and non-small cell cancer
- •Patients with known or increased risk factor for QTc prolongation
- •Treatment with any of the following:
- •Preoperative or adjuvant platinum-based or other chemotherapy for the disease under investigation
- •Prior treatment with neoadjuvant or adjuvant EGFR TKI
- •Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4
- •Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib
- •Any of the following cardiac criteria
- •Mean resting corrected QT interval >470 msec, obtained from 3 ECGs
- •Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
- •Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, or unexplained -sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval
- •Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD
研究组 & 干预措施
SoC SBRT + Durvalumab Therapy (Main Cohort)
SBRT
Durvalumab (PD-L1 monoclonal antibody) 1500 mg every 4 weeks [q4w] intravenously [iv] for up to 26 cycles or until progression or other discontinuation criteria are met.
干预措施: Durvalumab (Drug)
SoC SBRT + Osimertinib Therapy (Osimertinib cohort, single-arm, open-label separate cohort)
SBRT
Osimertinib 80mg every day [qd] for oral administration up to 36 months or until progression. Osimertinib treatment should start within 7 to 14 days after completion of SBRT
干预措施: (Osimertinib cohort, single-arm, open-label separate cohort) (Drug)
SoC SBRT + Placebo Therapy (Main Cohort)
SBRT
Placebo (matching placebo for infusion) every 4 weeks iv for up to 26 cycles or until progression or other discontinuation criteria are met.
干预措施: Placebo (Other)
结局指标
主要结局
Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1 in subpopulation of patients with Stage I/II NSCLC
时间窗: from randomization up to 6 years
Main Cohort
4-year Progression-Free Survival (4y-PFS) by ICR according to RECIST 1.1 criteria
时间窗: from treatment start up to 5 years
Osimertinib Cohort
次要结局
- Progression-Free Survival (PFS) assessed by BICR per RECIST 1.1 in all randomised patients with Stage I/II NSCLC(from randomization up to 6 years)
- Overall Survival (OS)(from randomization up to 7 years)
- Concentration of durvalumab in serum such as peak concentration and trough(12 weeks after last dose)
- Detection of ADA neutralising antibodies titers(up to 6 months after last dose)
- Assessment of AEs by CTCAE v 5.0 as measures of the safety, tolerability and compliance of osimertinib with SoC SBRT therapy(Up to 35 days after last dose)
- Health-related quality of life in patients treated with durvalumab with SoC SBRT compared to placebo with SoC SBRT using the EORTC QLQ-C30(from randomization up to 7 years)
- Proportion of patients alive and progression free at 24 months from randomisation (PFS24) assessed by BICR according to RECIST 1.1(at 24 months following randomization)
- Time to progression (TTP) assessed by BICR according to RECIST 1.1(from randomization up to 6 years)
- Time to death or distant metastasis (TTDM) assessed by BICR according to RECIST 1.1(from randomization up to 6 years)
- Time from randomisation to second progression (PFS2) as defined by local standard clinical practice(from randomization up to 7 years)
- Assessment of AEs by CTCAE v 5.0 as measures of the safety and tolerability of Durvalumab with SoC SBRT compared to placebo with SoC SBRT(up to 3 months after last dose)
- WHO performance status(from treatment start up to 5 years)
- ECG QT interval(Up to 156 weeks of treatment or treatment discontinuation)
- Overall Survival(from treatment start up to 5 years)
- Time To Progression (TTP)(from treatment start up to 5 years)
- Time to CNS progression(from treatment start up to 5 years)
- PFS2(from treatment start up to 5 years)
- Site(s) of disease progression(from treatment start up to 5 years)
- PFS by ICR using RECIST 1.1(from treatment start up to 5 years)