ctDNA-guIDEd consolidATION Immunotherapy After Chemoradiotherapy in Patients With Stage III Non-small Cell Lung Cancer
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 177
- 试验地点
- 32
- 主要终点
- To evaluate the efficacy of a personalized strategy of consolidation immunotherapy based on the assessment of MRD post-CRT in stage III NSCLC.
研究概览
简要总结
The reference treatment for locally advanced (stage III) non-small cell lung cancer (NSCLC) is concomitant chemoradiotherapy (CRT) followed by durvalumab consolidation for 1 year. This strategy is based on the results of the PACIFIC trial, which compared, in a randomized fashion after CRT, the superiority of treatment with durvalumab at a dose of 1500 mg every 4 weeks for 12 months to placebo in patients with non-progressive disease. The coprimary endpoints of this trial were progression-free survival (PFS) and overall survival (OS). This study was positive and showed a benefit in PFS and OS. However, less than half of patients (49%) received the full 12 months of durvalumab in this study, one-third of these discontinuations being related to toxicity. Furthermore, the prescription of durvalumab in this setting is not currently guided by any companion biomarker. As a result, the systematic prescription of a 12-month consolidation immunotherapy after CRT, without any selection criteria, leads to a possible overtreatment of patients whose survival would have been prolonged without additional treatment. These patients are systematically exposed to a potentially high and serious risk of toxicity in the course of immunotherapy. It is therefore crucial to move towards a more individualized approach in the prescription of consolidation immunotherapy after CRT in stage III NSCLC. This would ensure that the most appropriate treatment is delivered to patients who are likely to derive significant clinical benefit, while concurrently minimizing the exposure of other patients to potentially severe clinical toxicities. Additionally, such an approach would help protect healthcare systems from unnecessary economic burden, preventing the allocation of resources to treatments that offer limited therapeutic value.
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
- •Patients must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care. Patients must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
- •Age ≥18 years.
- •ECOG Performance Status of 0 or
- •Histologically proven unresectable locally advanced stage III NSCLC.
- •Diagnostic tumor tissue sample available for molecular biology analysis.
- •Measurable tumor according to RECIST1.
- •Patient eligible for concomitant curative CRT with authorization of two course of induction chemotherapy before the start of CRT. The minimum dose of radiotherapy is 60 Gy over 95% of tumor volumes.
- •FEV1≥40% of theoretical and PaO2≥60mmHg.
- •Hematological criteria: PNN ≥ 1.5x109/L and platelets ≥ 100x109/L, Hemoglobin ≥ 9 g/dL.
- •Creatinine clearance (according to the institution's standard method) ≥ 45 mL/min.
- •For women of childbearing potential (including women who have had a tubal ligation), serum pregnancy test must be performed and documented as negative within 14 days prior to C1D
- •Women of childbearing potential must remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study drugs. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries or uterus). Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method plus spermicide. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- •Men with female partners of childbearing potential or pregnant female partners, must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- •Patient has national health insurance coverage.
排除标准
- •Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R or L861X mutations in exon 21, G719A/S mutation in exon 18, exon 20 insertion) or HER2 exon 20 insertion (either tissue or plasma cfDNA mutation).
- •Known ALK, ROS1, gene rearrangement as assessed by immunohistochemistry, FISH or NGS (ADN or ARN) sequencing by local genetics and/or pathology laboratory.
- •Sequential CRT, defined as the start of thoracic irradiation after the administration of the third course of chemotherapy.
- •Pleural involvement or extra-thoracic tumor lesions.
- •Comorbidity contraindicating CRT.
- •Significant lesions of interstitial lung disease on chest CT or proven interstitial lung disease.
- •History of cancer in the last 3 years, or active cancer (with the exception of basal cell carcinoma of the skin and carcinoma in situ of the uterine cervix).
- •Previous thoracic radiotherapy.
- •Previous chemotherapy in the last 3 years.
- •Pregnant or breast-feeding woman.
- •Patient under legal protection.
- •Patient unable to follow the constraints of the trial.
- •Systemic corticosteroid therapy > 10mg/day of prednisone or equivalent and immunosuppressive treatment (with the exception of supplementary hydrocortisone treatment).
- •History of autoimmune disease, with the exception of:
- •Stable substituted hypothyroidism
- •Balanced type 1 diabetes
- •Vitiligo, psoriasis, lichen, without extra-dermatological involvement
- •History of anti-cancer treatment with immune checkpoint inhibitor.
- •Randomisation Criteria:
- •Patient without immediate progression after CRT.
- •Patient with a comprehensive CAPP-Seq profile established on tumor tissue and/or ctDNA before CRT.
- •Patient without contra-indication to immunotherapy.
- •Completion of CRT at a total dose of at least 60 Gy over 95% of tumour volumes and with at least two cycles of concurrent chemotherapy.
研究组 & 干预措施
Arm A : durvalumab
This arm is a non-comparative control group
干预措施: Durvalumab (Drug)
Arm B : durvalumab or no treatment
Patients in Arm B who are MRD positive will receive durvalumab. Patients in Arm B who are MRD negative will not receive durvalumab.
干预措施: CAPP-Seq technique (Diagnostic Test)
Arm B : durvalumab or no treatment
Patients in Arm B who are MRD positive will receive durvalumab. Patients in Arm B who are MRD negative will not receive durvalumab.
干预措施: Durvalumab (Drug)
结局指标
主要结局
To evaluate the efficacy of a personalized strategy of consolidation immunotherapy based on the assessment of MRD post-CRT in stage III NSCLC.
时间窗: 12 months after randomisation.
12-month PFS rate from randomization as assessed by an independent review committee (IRC). The primary endpoint is 12-month progression free survival (PFS). The analysis will be conducted in the FAS population. PFS is defined as the time between the date of randomization and the first date of documented progression, as determined by an IRC, or death due to any cause, whichever occurs first.
次要结局
- PFS as assessed by the investigator(Around 54 months)
- Overall Survival (OS)(Around 54 months.)
- Tolerance and safety(From time of informed consent through end of therapeutic period (consolidation treatment or no consolidation treatment) and up to 90 days after (maximum of 1 year and 3 months).)
- Time until definitive HRQoL deterioration (TUDD)(Around 54 months)
- General health status(Around 54 months)