A Study of Durvalumab as Consolidation Therapy in Non-Small Cell Lung Cancer Patients
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Interventions
- Other: Placebo
- Registration Number
- NCT03706690
- Lead Sponsor
- AstraZeneca
- Brief Summary
This 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, non-small cell lung cancer (Stage III), who have not progressed following definitive, platinum-based, chemoradiation therapy.
- Detailed Description
Approximately 400 patients will be randomized in a 2:1 to receive treatment with durvalumab or placebo therapy. The primary objective of this study is to assess the efficacy of durvalumab treatment compared with placebo in terms of PFS.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 407
- Age≥18 years
- Documented NSCLC and present with locally advanced, unresectable (Stage III) disease;
- Receipt of concurrent or sequential chemoradiation therapy,
- No progression following definitive, platinum-based, concurrent or sequential chemoradiation therapy
- World Health Organization (WHO) PS of 0 or 1;
- No prior exposure to any anti CTLA-4, anti-PD-1, anti-PD-L1, or anti PD L2 antibodies, excluding therapeutic anticancer vaccines
- Adequate organ and marrow function required
- Life expectancy of at least 12 weeks
- Tumor PD-L1 status, with the Ventana SP263 PD-L1 IHC assay determined by a reference laboratory, must be known prior to randomization.
- 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.
- History of allogeneic organ transplantation, or another primary malignancy, or active primary immunodeficiency.
- Active or prior documented autoimmune or inflammatory disorders
- Uncontrolled intercurrent illness 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
- Active infection including tuberculosis hepatitis B hepatitis C (HCV), or human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies).
- Mixed small cell and NSCLC histology, sarcomatoid variant
- Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 from the prior chemoradiation therapy.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Therapy Placebo Placebo (matching placebo for infusion every 4 weeks iv until clinical progression/deterioration or confirmed radiological progression) Durvalumab Therapy Durvalumab Durvalumab (PD-L1 monoclonal antibody)1500 mg every 4 weeks \[q4w\] intravenously \[iv\] until clinical progression/deterioration or confirmed radiological progression)
- Primary Outcome Measures
Name Time Method Progression-Free Survival (PFS) (Modified Intent-to-Treat [mITT] Set) Tumor scans performed at screening, every 8 weeks ±1 week up to 48 weeks, and then every 12 weeks ±1 week thereafter until confirmed PD. Assessed up to the DCO date 23-Jun-2024 (a maximum of approximately 2035 days) The PFS per Response Evaluation Criteria in Solid Tumors 1.1. (RECIST 1.1) using blinded independent central review (BICR) assessments was defined as the time from the date of randomization until the date of objective disease progression (PD) or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anti-cancer therapy prior to progression. The PD was defined as at least a 20% increase in the sum of diameters of target lesions (TLs) and an absolute increase of \>=5 millimeters (mm), taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) Assessed up to the DCO date 23-Jun-2024 (a maximum of approximately 2035 days) The OS was defined as the time from the date of randomization until death due to any cause regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy. Median OS was calculated using the Kaplan-Meier technique.
Progression-Free Survival (PFS) (Intent-to-Treat [ITT] Set) Tumor scans performed at screening, every 8 weeks ±1 week up to 48 weeks, and then every 12 weeks ±1 week thereafter until confirmed PD. Assessed up to the DCO date 23-Jun-2024 (a maximum of approximately 2035 days) The PFS per RECIST 1.1 using BICR assessments was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anti-cancer therapy prior to progression. The PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of \>=5 mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.
Percentage of Participants Alive at 24 Months (OS24) Month 24 OS was defined as the time from the date of randomization until death due to any cause regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy. The OS24 was defined as the Kaplan-Meier estimate of OS at 24 months after randomization.
Objective Response Rate (ORR) Tumor scans performed at screening, every 8 weeks ±1 week up to 48 weeks, and then every 12 weeks ±1 week thereafter until confirmed PD. Assessed up to the DCO date 23-Jun-2024 (a maximum of approximately 2035 days) The ORR per RECIST 1.1 using BICR was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) based on all participants in the subset of the analysis population including only those participants with measurable disease at baseline per BICR. The CR was defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10 mm. The PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters as long as criteria for PD are not met.
Duration of Response (DoR) Tumor scans performed at screening, every 8 weeks ±1 week up to 48 weeks, and then every 12 weeks ±1 week thereafter until confirmed PD. Assessed up to the DCO date 23-Jun-2024 (a maximum of approximately 2035 days) The DoR per RECIST 1.1 using BICR was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of PD. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of \>=5 mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. The DoR was calculated using the Kaplan-Meier technique.
Percentage of Participants Alive and Progression-Free at 12 and 18 Months (PFS12 and PFS18) Months 12 and 18 The PFS per RECIST 1.1 using BICR assessments was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anti-cancer therapy prior to progression. The PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of \>=5 mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. The PFS12 and PFS18 were defined as the Kaplan-Meier estimate of PFS per RECIST 1.1 as assessed by the Investigator at 12 and 18 months, respectively and both were obtained using the algorithm for the RECIST 1.1 site Investigator tumor data.
Serum Concentration of Durvalumab End of infusion on Cycle 1 Day 1, pre-infusion on Cycles 2 and 4 Day 1 and Month 3 follow-up (each cycle=28 days) Blood samples were collected to determine the concentration of durvalumab.
Time From Randomization to Second Progression (PFS2) Tumor scans performed at screening, every 8 weeks ±1 week up to 48 weeks, and then every 12 weeks ±1 week thereafter until confirmed PD. Assessed up to the DCO date 23-Jun-2024 (a maximum of approximately 2035 days) PFS2 was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy, or death. The date of the second progression was recorded by the Investigator and defined according to local standard clinical practice and could have involved any of objective radiological imaging, symptomatic progression, or death. Median time to PFS2 was calculated using the Kaplan-Meier technique.
Time to Death or Distant Metastases (TTDM) Tumor scans performed at screening, every 8 weeks ±1 week up to 48 weeks, and then every 12 weeks ±1 week thereafter until confirmed PD. Assessed up to the DCO date 23-Jun-2024 (a maximum of approximately 2035 days) TTDM as per RECIST 1.1 using BICR was defined as the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis was defined as any new lesion that was outside of the radiation field according to RECIST 1.1. Median TTDM was calculated using the Kaplan-Meier technique.
Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab Pre-dose on Day 1 of Cycles 1, 2 and 4 (each cycle=28 days) Blood samples were collected to determine the presence of ADAs and ADA-neutralizing antibodies (nAb) for durvalumab using validated assays. ADA prevalence was defined as the number of participants with positive ADA result at any time, baseline or post-baseline. ADA incidence was defined as either treatment-induced (post-baseline ADA positive only) or treatment-boosted ADA (baseline positive ADA titer that was boosted to \>=4-fold during the study period). Treatment-induced ADA was defined as ADA positive only post-baseline and not detected at baseline. Persistently positive was defined as having at least 2 post-baseline ADA positive assessments with at least 16 weeks between the first and last positive assessment, or ADA positive at the last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment without fulfilling the conditions for persistently positive.
Change From Baseline in Patient-Reported Symptoms as Assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ) at Week 132 Baseline (Day 1) and Week 132 Patient reported outcomes for 5 disease related symptoms was assessed using EORTC QLQ-Core 30 (C30) items questionnaire (fatigue, appetite loss) and EORTC QLQ-Lung Cancer module 13 (LC13) (dyspnoea, cough and pain in chest).An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, functional scales, and global health status scale with higher scores on global health status/QoL and functioning scales representing better health status/function, but higher scores on symptom scales/items representing greater symptom severity. An improvement in symptoms were indicated by a negative change in score from baseline. A positive change in score from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change was defined as change from baseline of \>=10. Change from baseline in C30: global health status/QoL, physical functioning, fatigue, appetite loss and LC13: dyspnoea, cough and pain in chest are presented.
Number of Participants With Positive Programmed Death Ligand 1 (PD-L1) Status Based on Overall Survival, Progression-Free Survival and Objective Response Rate Up to 9 years Blood samples will be collected for clinical biomarker testing and a tumor specimen will be collected as per tumor specimen collection requirements. The specimen will be evaluated by immunohistochemistry to determine the expression of tumor specific antigens and immune markers. The PD-L1 is a biomarker and data for number of participants with its positive status will be presented.
Trial Locations
- Locations (1)
Research Site
🇹🇷Malatya, Turkey