CTRI/2018/07/014783进行中（未招募）3 期
A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab Given Concurrently with Platinum-based Chemoradiation Therapy in Patients with Locally Advanced, Unresectable Non-small Cell Lung Cancer (Stage III)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 300
- 试验地点
- 9
- 主要终点
- To assess the efficacy of durvalumab + Standard of Care Chemo Radiation Therapy compared with placebo + Standard of Care Chemo Radiation in terms of Progression Free Survival and Objective Response Rate
研究概览
简要总结
This is a Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab Given Concurrently with Platinum-based Chemoradiation Therapy in Patients with Locally Advanced, Unresectable Non-small Cell Lung Cancer (Stage III)
Patients will be randomized in a 2:1 ratio to durvalumab plus SoC CRT or placebo plus SoC CRT. Patients will be stratified by age (<65 vs ≥65 years) and stage (IIIA vs IIIB/C). Durvalumab/ Placebo will be administered via intravenous (IV) infusion every 4 weeks (Q4W).
All patients will receive 1 of the following platinum-based SoC chemotherapy options, based on Investigator discretion, in addition to radiation therapy: cisplatin/etoposide, carboplatin/paclitaxel, pemetrexed/cisplatin, or pemetrexed/carboplatin. Chemotherapy treatment regimens are outlined in the protocol.
Patients will also receive durvalumab 1500 mg or placebo every 4 weeks via intravenous infusion concurrent with SoC CRT (ie, starting on Cycle 1 Day 1 [±3 days]). Patients with complete response (CR), partial response (PR), or SD following completion of SoC CRT will continue to receive durvalumab/placebo as consolidation treatment. Patients with RECIST 1.1’defined radiological progressive disease at the 16 ’week tumor evaluation following completion of SoC CRT will proceed to follow-up
The clinical activity associated with potentiating the proinflammatory effects of CRT suggests that giving durvalumab in combination with CRT may have clinical benefits, including increasing the response rate to CRT, improving the CR rate, and decreasing the number of patients who progress on CRT.
Safety observations to date have demonstrated that concurrent administration of CRT and immunotherapy has generally been well tolerated, with toxicities comparable to administration of either agent alone. The safety of concurrent administration of durvalumab and CRT is further supported by results from the PACIFIC study, which showed that durvalumab administered within 42 days of completion of CRT had a well ’tolerated and manageable safety profile that was consistent with the established safety profile to date.
Therefore, the overall benefit-risk assessment supports the proposed study to evaluate the efficacy and safety of concurrent administration of durvalumab and CRT.
研究设计
- 研究类型
- Interventional
- 分配方式
- Stratified randomization
- 盲法
- Double Blind Double Dummy
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Informed consent 1.Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 2.Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses. 3.18 years or older at the time of signing the ICF. In Japan, patients must be 20 years or older at the time of signing the ICF. 4.Histologically or cytologically documented NSCLC who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology 2016]). ï€Except for overt cT4 disease, nodal status N2 or N3 should be proven by biopsy, via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. Absent biopsy, nodal status should be confirmed with whole body F-fluoro-deoxyglucose positron emission tomography, plus contrast-enhanced computed tomography (CT) in addition to or in combination with PET. ï€Mandatory brain magnetic resonance imaging (MRI preferred) or high-quality brain CT with IV contrast at the time of staging. 5.World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrollment and randomization. 6.Patients with at least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 Target Lesion (TL) at baseline. Tumor assessment by CT or MRI must be performed within 28 days prior to randomization. 7.Tumor sample requirements: i.Mandatory provision of an archived tumor tissue block (or at least 15 newly cut unstained slides) less than or equal to 3 years old. If an archival sample is not available, provision of a recent (less than or equal to 3 months) tumor biopsy is mandated. ii.The provision of an additional recent (less than or equal to 3 months) tumor biopsy is optional, provided that a biopsy procedure is technically feasible and the procedure is not associated with unacceptable clinical risk. 8.Must have a life expectancy of at least 12 weeks at randomization 9.Pre- or post-bronchodilator forced expiratory volume 1 of 1.0 L or greater than 40 percentage predicted value and diffusing capacity of the lung for carbon monoxide greater than 30 percentage predicted value. Pulmonary function testing results for up to 8 weeks prior to registration are permitted. 10.Adequate organ and marrow function at enrollment and randomization as defined below: iii.Hemoglobin greater than or equal to 9.0 g/dL iv.Absolute neutrophil count greater than 1.5 × 109/L v.Platelet count greater than 100 × 109/L vi.Serum bilirubin less than or equal to 1.5 × upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician. vii.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 × ULN; for patients with hepatic metastases, ALT and AST less than or equal to 5 × ULN. viii.Measured creatinine clearance (CL) greater than 40 mL/min or calculated CL greater than 40 mL/min as determined by Cockcroft-Gault (using actual body weight) 11.Genetics research study (optional) For inclusion in the optional (DNA) genetics research study, patients must fulfil the following criteria:.
- •Provide informed consent for the genetic sampling and analyses. If a patient declines to participate in the genetics research, there will be no penalty or loss of benefit to the patient. A patient who declines genetics research participation will not be excluded from any other aspect of the main study. 12.Body weight greater than 30 kg at enrollment and randomization 13.Male or female 14.Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: i.Women greater than 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). ii.Women greater than or equal to 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses greater than 1 year ago, had chemotherapy-induced menopause with last menses greater than 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
排除标准
- •Patients should not enter the study if any of the following exclusion criteria are fulfilled: Medical conditions 1.History of allogeneic organ transplantation 2.Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [example colitis or Crohns disease]diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]).
- •The following are exceptions to this criterion: i.Patients with vitiligo or alopecia ii.Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement iii.Any chronic skin condition that does not require systemic therapy iv.Patients without active disease in the last 5 years at randomization may be included but only after consultation with the study physician v.Patients with celiac disease controlled by diet alone 3.Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent 4.History of another primary malignancy except for vi.Malignancy treated with curative intent and with no known active disease greater than or equal to 5 years before the first dose of IP and of low potential risk for recurrence vii.Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease viii.Adequately treated carcinoma in situ without evidence of disease 5.History of leptomeningeal carcinomatosis 6.History of active primary immunodeficiency 7.Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies).
- •Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.
- •Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for HCV RNA 8.Mixed small cell and NSCLC histology.
- •9.Known allergy or hypersensitivity to any of the IPs or any of the IP excipients.
- •10.Any medical contraindication to treatment with platinum-based doublet chemotherapy as listed in the local labelling.
- •11.Patients whose radiation treatment plans are likely to encompass a volume of whole lung receiving greater than or equal to 20 Gy in total (V20) of more than 35 percentage of lung volume.
- •V20s up to 37% will be permitted and viewed as a minor deviation, provided that the treating radiation oncologist believes this level of exposure is within patient tolerance.
- •12.Planned radiation cardiac dose V50 greater than 25 percentage.
- •13.Patients who have disease considered for surgical treatment as part of their care plan, such as Pancoast or superior sulcus tumors Prior/concomitant therapy 14.Receipt of prior or current cancer treatment, including but not limited to, radiation therapy, investigational agents, chemotherapy, and mAbs.
- •Prior surgical resection (ie, Stage I or II) is permitted.
- •15.Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
- •Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.
- •16.Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
- •Note: Local surgery of isolated lesions for palliative intent is acceptable.
- •17.Prior exposure to immune-mediated therapy, including but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti PD L2 antibodies, excluding therapeutic anticancer vaccines.
- •18.Current or prior use of immunosuppressive medication within 14 days before the first dose of IP.
- •The following are exceptions to this criterion: i.Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) ii.Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent iii.Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) Prior/concurrent clinical study experience 19.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- •20.Previous IP assignment in the present study 21.Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study.
- •22.Participation in another clinical study with an IP during the 4 weeks prior to randomization.
- •23.Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
- •Other exclusions 24.Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of IP.
- •25.Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions, and requirements.
- •26.Genetics research study (optional): Exclusion criteria for participation in the optional (DNA) genetics research component of the study include: i.Previous allogeneic bone marrow transplant.
- •ii.Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection.
结局指标
主要结局
To assess the efficacy of durvalumab + Standard of Care Chemo Radiation Therapy compared with placebo + Standard of Care Chemo Radiation in terms of Progression Free Survival and Objective Response Rate
时间窗: Approximately 4 years
次要结局
- To assess the PK of durvalumab when in combination with CRT(Overall Survival (OS) (Time frame-Approximately 4 years))
- To investigate the immunogenicity of durvalumab(Overall Survival (OS) (Time frame-Approximately 4 years))
- To investigate the immunogenicity of durvalumab when in combination with CRT(Overall Survival (OS) (Time frame-Approximately 4 years))
- To assess the safety and tolerability profile of durvalumab plus SoC CRT compared with placebo plus SoC CRT(Overall Survival (OS) (Time frame-Approximately 4 years))
- To investigate the relationship between durvalumab PK exposure and clinical outcomes, efficacy, AEs, and/or safety parameters, if deemed appropriate(Overall Survival (OS) (Time frame-Approximately 4 years))
- To assess patients’ overall impression of the severity of their cancer symptoms using PGIS(Overall Survival (OS) (Time frame-Approximately 4 years))
- To describe and evaluate resource use associated with durvalumab treatment and underlying disease(Overall Survival (OS) (Time frame-Approximately 4 years))
- To explore the impact of treatment and disease state on health state utility using the EQ-5D-5L(Overall Survival (OS) (Time frame-Approximately 4 years))
- To investigate the relationship between a patient’s PD-L1 expression and spatial distribution within the tumor microenvironment and efficacy outcomes with durvalumab(Overall Survival (OS) (Time frame-Approximately 4 years))
- To collect blood and tissue samples, or leverage residual samples, for analysis of peripheral and tumoral biomarkers(Overall Survival (OS) (Time frame-Approximately 4 years))
- To explore the relationship(s) between a patient’s biomarker status and durvalumab PK exposure and clinical outcomes before and after treatment(Overall Survival (OS) (Time frame-Approximately 4 years))
- To collect and store DNA from tissue and/or blood according to each country’s local and ethical procedures for future exploratory research into genes/genetic variation that may influence response (ie, distribution, safety, tolerability, and efficacy) to IPs and/or susceptibility to disease (optional)(Overall Survival (OS) (Time frame-Approximately 4 years))
- To assess the efficacy of durvalumab PLUS(SoC CRT compared with placebo PLUS SoC CRT)
研究者
研究点 (9)
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