CTRI/2019/02/017798招募中3 期
A Phase III Randomized Double-Blind Placebo-Controlled Multicenter study of Durvalumab as Consolidation Therapy in patients with locally advanced unresectable Non-Small Cell Lung Cancer (Stage III) who have not progressed following definitive platinum-based chemoradiation therapy
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 360
- 试验地点
- 8
- 主要终点
- To assess the efficacy of Durvalumab treatment compared with placebo in terms of Progression Free Survival
研究概览
简要总结
This study is a Phase III, randomised, double-blind, placebo-controlled, multicentre study assessing the efficacy and safety of durvalumab compared with placebo as consolidation therapy in patients with locally advanced, unresectable NSCLC (Stage III) who have not progressed following definitive, platinum-based, chemoradiation therapy.
Approximately 360 patients with locally advanced, unresectable NSCLC (Stage III) who received cCRT or sCRT will be randomised globally. These patients will be in complete response (CR), partial response (PR), or have stable disease (SD) following definitive, platinum based, concurrent or sequential chemoradiation therapy.
Patients must have histologically or cytologically documented NSCLC and present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology. The number of patients with an EGFR mutation or ALK rearrangement will be capped at approximately 15% of the total number of patients randomised. The study will maintain a balance of approximately 1:1 between the cCRT and sCRT patient population with the majority of patients to be recruited in China.
Patients will be randomised in a 2:1 ratio (durvalumab to placebo) to 1 of 2 arms:
· Durvalumab q4w intravenously [IV] until clinical progression/deterioration or confirmed radiological progression)
· Placebo (matching placebo) for infusion q4w IV until clinical progression/deterioration or confirmed radiological progression)
Randomisation will be stratified by the level of PD-L1 expression (PD-L1 <1% or PD-L1≥1%] and prior therapy (cCRT or sCRT). Patients must not have progressed following definitive, platinum-based, concurrent or sequential CRT. For those patients randomised to the placebo arm, no crossover to the durvalumab arm is permitted; similarly, those patients randomised to the durvalumab arm cannot crossover to the placebo arm.
Tumour assessments using computed tomography (CT)/magnetic resonance imaging (MRI) will be performed. RECIST 1.1 measurements (using BICR assessments) will be used to derive the primary variable of PFS and secondary variables of ORR, DoR, PFS12, and PFS18.
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
- •Capability to give signed informed consent that 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 Histologically or cytologically documented NSCLC and present with locally advanced unresectable (Stage III) disease (according to Version 8 of the (IASLC Staging Manual in Thoracic Oncology]). Positron emission tomography/CT, MRI of the brain, and endobronchial ultrasound with biopsy are highly encouraged at diagnosis. 4.Receipt of concurrent or sequential chemoradiation therapy, which must be completed within 1 to 28 days prior to first dose of IP in the study. -For cCRT, patients must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy. The last dose of chemotherapy must be prior to, or concurrent with, the final dose of radiation. Consolidation chemotherapy after radiation is not permitted, but no more than 2 cycles of induction chemotherapy prior to cCRT is acceptable. -For sCRT, patients must have received at least 2 cycles of platinum-based chemotherapy before radiation therapy. The interval between administration of the last dose of chemotherapy regimen and start of RT must be no more than 6 weeks. Consolidation chemotherapy after radiation is not permitted. (i) Note: If a patient receives only 1 cycle of platinum-based chemotherapy concurrent with radiation treatment, this patient will be eligible for the study to participate in the sCRT stratum. -The platinum-based chemotherapy regimen must contain cisplatin or carboplatin and 1 of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel), or pemetrexed, according to the local SoC regimens. (Gemcitabine is not included.) -Patients must have received a total dose of radiation of 60 Gy ±10% (54 to 66 Gy) to be randomised as part of the chemoradiation therapy. Study sites are encouraged to adhere to the following mean organ radiation dosing: (i) Mean lung dose must be <20 Gy, and/or V20 must be <35% (ii) Mean oesophagus dose must be <34 Gy (iii) Heart V45 must be <35%, or V30 must be <30% ï€ Study sites should be aware of the recent RTOG 0617 Trial data demonstrating that doses higher than 60 Gy may be associated with greater toxicity and worse efficacy.
- •No progression following definitive, platinum-based, concurrent or sequential chemoradiation therapy 6.Tumor PD-L1 status, with the Ventana SP263 PD-L1 IHC assay determined by a reference laboratory, must be known prior to randomization. Patient with unknown PD-L1 status is not eligible for the study. “Unknown†refers to (1) insufficient sample which is not able to be analyzed, or (2) sample could be analyzed but results not interpretable.
- •Documented EGFR and ALK status (locally or centrally) at Screening. If the local laboratory will perform the test, a well-validated, local regulatory-approved kit must be used. -EGFR and ALK status must be available prior to randomisation. After approximately 15% EGFR or ALK mutant patients have been randomised, the incoming patients with EGFR or ALK mutation will not be enrolled. 8.Tumour sample requirements are as follows: Provision of a tumour tissue sample (newly acquired sample ≤3 months old is preferred, but an archived sample ≤6 months old is acceptable) in a quantity sufficient to allow for analysis. Study subject should not have received any intervening systemic therapy other than chemoradiotherapy for Stage III disease as described above. 9.World Health Organization (WHO) PS of 0 or 1 at enrolment 10.No prior exposure to any anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines 11.Adequate organ and marrow function as defined below. Absolute neutrophil count, platelet count, and haemoglobin criteria cannot be met with transfusion or growth factor support administered within 14 days before randomisation. -Haemoglobin ≥9 g/L -Absolute neutrophil count >1.5 × 109/L (1500 per mm3) -Platelet count >100 × 109/L (100000 per mm3).
- •Serum bilirubin ≤1.5× the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of haemolysis or hepatic pathology), who will be allowed in consultation with their primary physician. -Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN -Serum creatinine clearance (CL) >40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine CL
- •Life expectancy of at least 12 weeks at Day 1 13.WT >30 kg.
排除标准
- •Patients should not enter the study if any of the following exclusion criteria are fulfilled: 1.History of allogeneic organ transplantation 2.Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s 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: -Patients with vitiligo or alopecia -Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement -Any chronic skin condition that does not require systemic therapy -Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician -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, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, 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 History of another primary malignancy except for -Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of investigation product (IP) and of low potential risk for recurrence -Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease -Adequately treated carcinoma in situ without evidence of disease 5.History of active primary immunodeficiency
- •Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis testing inline with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C (HCV), or human immunodeficiency virus(positive human immunodeficiency virus [HIV] 1/2 antibodies).
- •Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.
- •Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- •7.Mixed small cell and NSCLC histology 8.Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 from the prior chemoradiation therapy.
- •9.Patients with Grade ≥2 pneumonitis from prior chemoradiation therapy
- •Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients Prior/concomitant therapy
- •Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment other than those under investigation in this study
- •Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
- •Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
- •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 and placement of vascular access are acceptable.
- •The following are exceptions to this criterion: -Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection) -Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent -Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) -Systemic steroid administration required as prophylaxis against or to manage toxicities arising from chemotherapy and/or radiotherapy delivered as part of the chemoradiation therapy for locally advanced NSCLC Prior/concurrent clinical study experience
- •Participation in another clinical study with an IP administered in the last 4 weeks prior to randomization.
- •Previous IP assignment in the present study
- •Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the Follow-up Period of an interventional study
- •Prior randomisation or treatment in a previous durvalumab ± tremelimumab clinical study regardless of treatment arm assignment Other exclusions 19.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 durvalumab monotherapy 20.Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
结局指标
主要结局
To assess the efficacy of Durvalumab treatment compared with placebo in terms of Progression Free Survival
时间窗: Progression Free Survival Time frame approximately 5 years
次要结局
- To further access the efficacy of Durvalumab compared with Placebo in terms of OS(OS analysis will occur when approximately 255 death events have occurred)
- •To further assess the efficacy of durvalumab compared with placebo in terms of OS24, ORR, DoR, PFS12, PFS18, PFS2, and TTDM
- To assess the PK of Durvalumab(Time Frame approximately 5 years)
- To investigate the immunogenicity of Durvalumab(Time Frame Approximately 5 years)
- To assess symptoms and health related quality of life in patients treated with Durvalumab compared with placebo using EORTC QLQ C30 v3 and QLQ LC13(Overall Survival Time Frame approximately 5 years)
- To investigate the relationship between a patients tissue TMB and efficacy outcomes with Durvalumab(Time frame approximately 5 years)
- To investigate the relationship between a patients baseline tumor PD L1 expresssion and efficacy outcome with durvalumab compared with placebo(Time Frame approximately 5 years)
研究者
研究点 (8)
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