NCT05170204进行中（未招募）3 期
A Phase I-III, Multicenter Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Patients Selected According to Biomarker Status, With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 68
- 试验地点
- 176
- 主要终点
- Progression-free survival (PFS)
研究概览
简要总结
This study will evaluate the efficacy and safety of multiple therapies in participants with locally advanced, unresectable, Stage III NSCLC with eligible biomarker status as determined by Version 8 of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) NSCLC staging system.
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
- None
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
- •(All Cohorts):
- •Body weight ≥ 30 kilograms (kg) at screening
- •Willingness and ability to use the electronic device(s) or application(s) for the electronic patient-reported outcome (PRO)
- •Whole-body positron emission tomography/computed tomography scan (PET/CT) (from the base of skull to mid-thighs) for the purposes of staging, performed prior and within 42 days for Cohort A2 (ROS1 positive) and 50 days for Cohort A1 (ALK positive) of the first dose of concurrent chemoradiotherapy (cCRT) or sequential chemoradiotherapy (sCRT)
- •Histologically or cytologically documented locally advanced, unresectable Stage III NSCLC of either squamous or non-squamous histology
- •Prior receipt of at least two prior cycles of platinum-based chemotherapy given cCRT; or at least two prior cycles of platinum-based chemotherapy given prior to radiotherapy (sCRT)
- •The RT component in the cCRT or sCRT must have been at a total dose of radiation of 60 (+/-10%) Gy (54 Gy to 66 Gy) administered by intensity-modulated radiotherapy (preferred) or three dimension (3D)-conforming technique
- •No disease progression during or following platinum-based cCRT or sCRT
- •Life expectancy ≥ 12 weeks
- •Confirmed availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen
- •Tumor programmed death-ligand 1 (PD-L1) status (TC score < 1% vs. ≥ 1% vs. unknown) as determined using the VENTANA PD-L1 IHC SP263 assay (preferred) or the Dako PD-L1 IHC 22C3 pharmDx assay
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- •Adequate hematologic and end-organ function
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined by the protocol
- •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined by the protocol
- •Inclusion criteria specific to Cohort A1:
- •Documented ALK fusion positivity by an eligible result from: centralized multiplex molecular testing of tumor tissue at the Sponsor's designated central laboratory under Study BX43361 or prior tissue-based testing performed in an accredited or certified laboratory
- •Inclusion criteria specific to Cohort A2:
- •Documented ROS1 fusion positivity by an eligible result from: centralized multiplex molecular testing of tumor tissue at the Sponsor's designated central laboratory under Study BX43361 or available results from a Sponsor pre-approved local, appropriately validated ROS1 fusion test on tumor tissue performed in a Clinical Laboratory Improvement Amendments certified or equivalent laboratory
- •Ability to swallow entrectinib intact, without chewing, crushing, or opening the capsules
排除标准
- •(All Cohorts):
- •Any history of previous NSCLC and/or any history of prior treatment for NSCLC (participants must be newly diagnosed with unresectable Stage III disease)
- •Any evidence of Stage IV disease, including, but not limited to, the following: pleural effusion, pericardial effusion, brain metastases, history of intracranial hemorrhage or spinal cord hemorrhage, bone metastases, distant metastases
- •If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (T4 disease): when pleural fluid is visible on both the CT scan and chest X-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative; participants with exudative pleural effusions are excluded regardless of cytology; participants with effusions that are minimal (i.e., not visible on chest X-ray) that are too small to safely tap are eligible
- •NSCLC known to have a known or likely oncogenic-driver mutation in the epidermal growth factor receptor (EGFR) gene, as identified by site local testing or Sponsor central testing
- •Liver disease, characterized by any of the following: impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease, such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices or active viral or active autoimmune, alcoholic, or other types of acute hepatitis
- •Positive hepatitis B surface antigen (HBsAg) test at screening
- •Participants known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded with the following exception: participants who are HCV Ab positive but HCV ribonucleic acid (RNA) negative due to prior treatment or natural resolution are eligible
- •HIV infection: participants are excluded if not well-controlled as defined by the protocol
- •Known active tuberculosis
- •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest CT scan
- •Grade ≥ 2 pneumonitis from prior cCRT or sCRT
- •Any Grade > 2 unresolved toxicity from prior cCRT or sCRT
- •Any gastrointestinal (GI) disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection
- •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
- •Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: participants with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study; participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
- •History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer
- •Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
- •Major surgical procedure, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
- •Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
- •Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the final dose of study treatment
- •Treatment with investigational therapy within 28 days prior to initiation of study treatment
- •Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with exceptions defined by the protocol
- •Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein 4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- •Prior allogeneic stem cell or solid organ transplantation
- •Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study
- •Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of patient safety or study results
- •Any prior Grade ≥ 3 immune-mediated adverse event or any unresolved Grade > 1 immune-mediated adverse event while receiving any previous immunotherapy agent other than immune checkpoint blockade agents
- •Exclusion criteria specific to Cohort A1:
- •Presence of clinically symptomatic interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention)
- •NSCLC known to have one or more of the following ALK point mutations, as identified by site local testing or Sponsor central testing: I1171X (where X is any other amino acid), V1180L, G1202R
- •Symptomatic bradycardia
- •Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina; participants with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
- •Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- •Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- •Prior treatment with ALK inhibitors
- •History of hypersensitivity to alectinib, durvalumab, or any of their excipients
- •Inability to swallow oral study drug
- •Known hereditary problems of galactose intolerance, a congenital lactase deficiency, or glucose-galactose malabsorption
- •Pregnancy or breastfeeding, or intending to become pregnant during the study treatment or within 90 days after the final dose of alectinib or durvalumab
- •Exclusion criteria specific to Cohort A2:
- •Symptomatic bradycardia
- •Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina; participants with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
- •Left ventricular ejection fraction less than or equal to 50% observed during the screening for the study
- •History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 450 ms from ECGs performed at least 24 hours apart)
- •History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome)
- •Familial or personal history of congenital bone disorders or bone metabolism alterations
- •Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of the treatment
- •Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- •Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- 另有 6 项未显示
研究组 & 干预措施
Cohort A1: Anaplastic Lymphoma Kinase (ALK)-positive (Alectinib Arm)
Experimental
Participants will receive alectinib 600 milligrams (mg) orally twice daily until completion of treatment period (3 years), or until disease progression, unacceptable toxicity, participant or physician decision to discontinue, or death, whichever occurs first
干预措施: Alectinib (Drug)
Cohort A1: ALK-positive (Durvalumab Arm)
Active Comparator
Participants will receive 1500 mg of intravenous (IV) durvalumab every 4 weeks (Q4W) until completion of treatment period (1 year) or until disease progression, unacceptable toxicity, participant or physician decision to discontinue, or death, whichever occurs first
干预措施: Durvalumab (Drug)
Cohort A2: ROS 1-positive (Durvalumab Arm)
Active Comparator
Participants will receive 1500 mg of IV durvalumab Q4W until completion of treatment period (1 year) or until disease progression, unacceptable toxicity, participant or physician decision to discontinue, or death, whichever occurs first
Cohort A2 has been closed to enrollment.
干预措施: Durvalumab (Drug)
Cohort A2: ROS Proto-oncogene 1 (ROS 1)-positive (Entrectinib Arm)
Experimental
Participants will receive entrectinib 600 mg orally once daily until completion of treatment period (3 years), or until disease progression, unacceptable toxicity, participant or physician decision to discontinue, or death, whichever occurs first.
Cohort A2 has been closed to enrollment.
干预措施: Entrectinib (Drug)
结局指标
主要结局
Progression-free survival (PFS)
时间窗: From randomization to the first documented disease progression as determined by blinded independent central review (BICR) per Response Evaluation Criterial in Solid Tumors (RECIST) v1.1, or death from any cause, whichever occurs first (up to 3 years)
Progression-free Survival (PFS), as Determined by Blinded Independent Central Review (BICR) per Response Evaluation Criterial in Solid Tumors Version 1.1 (RECIST V1.1)
时间窗: From randomization to the first documented disease progression or death from any cause, whichever occurs first (up to 3 years)
次要结局
- Time to central nervous system (CNS) progression(From randomization to the first occurrence of disease progression in the CNS as determined by BICR per RECIST v1.1 (up to 3 years))
- Time to Central Nervous System (CNS) Progression, as Determined by BICR per RECIST v1.1(From randomization to the first occurrence of disease progression in the CNS (up to 3 years))
- Distant Metastasis-free Survival (DMFS), as Determined by BICR per RECIST v1.1(From randomization to the first occurrence of distant metastasis or death, whichever occurs first (up to 3 years))
- Objective Response Rate (ORR), as Determined by the Investigator per RECIST v1.1(Up to 3 years)
- PFS, as Determined by the Investigator per RECIST v1.1(From randomization to the first documented disease progression or death from any cause, whichever occurs first (up to 3 years))
- Duration of response (DOR), as Determined by the Investigator per RECIST v1.1(From the first documented CR or PR to the first documented disease progression or death, whichever occurs first (up to 3 years))
- ORR, as Determined by BICR per RECIST v1.1(Up to 3 years)
- DOR, as Determined by BICR per RECIST v1.1(From the first documented CR or PR to the first documented disease progression or death, whichever occurs first (up to 3 years))
- Overall Survival (OS)(From randomization to death from any cause (up to 5 years))
- Time to CNS Progression, as Determined by the Investigator per RECIST v1.1(From randomization to the first occurrence of disease progression in the CNS (up to 3 years))
- DMFS, as Determined by the Investigator per RECIST v1.1(From randomization to the first occurrence of distant metastasis or death, whichever occurs first (up to 3 years))
- Time-to-confirmed Deterioration (TTCD), as Measured Using the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) in Physical and Role Functioning Scales(From randomization to the first deterioration of ≥ 10 points that is either maintained for two consecutive assessments or followed by death from any cause within 3 weeks (up to 3 years))
- TTCD, as Measured Using the EORTC QLQ - Lung Cancer 13-item Questionnaire (LC13) in Cough, Chest Pain and Dyspnea Symptom Scales(From randomization to the first deterioration of ≥ 10 points that is either maintained for two consecutive assessments or followed by death from any cause within 3 weeks (up to 3 years))
- Proportion of Participants Who Have Maintained or Improved Baseline Health as Measured by EORTC QLQ-C30 Physical Functioning and Role Functioning Scales(At 5, 11, and 17 months)
- Proportion of Participants Who Have Maintained or Improved From Their Baseline Health in Cough, Chest Pain, and Dyspnea Symptoms as Measured Using the EORTC QLQ-LC13(At 5, 11, and 17 months)
- Percentage of Participants With Adverse Events (AEs)(Up to 3 years)
- Distant metastasis-free survival (DMFS)(From randomization to the first occurrence of distant metastasis or death (whichever occurs first) as determined by BICR per RECIST v1.1 (up to 3 years))
- Objective response rate (ORR), defined as the percentage of participants with measurable disease who attain a complete response (CR) or partial response (PR) as determined by the investigator per RECIST v1.1(Up to 3 years)
- PFS(From randomization to the first documented disease progression as determined by the investigator per RECIST v1.1, or death from any cause, whichever occurs first (up to 3 years))
- Duration of response (DOR)(From the first documented CR or PR to the first documented disease progression or death (whichever occurs first) as determined by the investigator per RECIST v1.1 (up to 3 years))
- ORR, defined as the percentage of participants with measurable disease who attain a CR or PR as determined by BICR per RECIST v1.1(Up to 3 years)
- DOR(From the first documented CR or PR to the first documented disease progression or death (whichever occurs first) as determined by BICR per RECIST v1.1 (up to 3 years))
- Overall survival (OS)(From randomization to death from any cause (up to 5 years))
- Time to CNS progression(From randomization to the first occurrence of disease progression in the CNS as determined by the investigator per RECIST v1.1 (up to 3 years))
- Time-to-confirmed deterioration (TTCD)(From randomization to the first deterioration of >/= 10 points that is either maintained for two consecutive assessments or followed by death from any cause within 3 weeks (up to 3 years))
- Proportion of participants who have maintained or improved baseline health as measured by the European Organisation for the Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 physical functioning and role functioning scales(5, 11, and 17 months)
- Proportion of participants who have maintained or improved from their baseline health in cough, chest pain, and dyspnea symptoms as measured using the EORTC QLQ-LC13(5, 11, and 17 months)
- Percentage of participants with adverse events (AEs)(Up to 3 years)
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