The DURATION study is an open label, treatment stratified, and randomized phase II study (Figure 1) enrolling patients with histologically confirmed NSCLC (adenocarcinoma and squamous) stage four (metastatic) prior to any systemic treatment. All procedures and time frames displaced in figure 1 and schedule of assessment (Table 3) are developed according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). Additional file 1 contains the complete SPIRIT checklist.
The DURATION trial is a multicenter trial, recruiting patients from approximately 30 sites across Germany. A full list of sites can be obtained at clinicaltrials.gov (NCT03345810).
The primary objective is to investigate the safety and tolerability of sequential therapy consisting of standard of care single agent or doublet chemotherapy followed by durvalumab in comparison to standard of care single-agent or doublet chemotherapy in frail and/or elderly patients.
Secondary objectives are to collect information on efficacy, safety and quality of life parameters and to investigate the utility of geriatric assessments for treatment guidance. Geriatric assessment and quality of life parameters will be collected before and at distinct timepoints during the treatment course.
Exploratory objectives are to identify potential predictive biomarkers for efficacy variables. To this end, tissue collection and blood sampling will be performed before and during course of disease/treatment. The blood and tissue samples will be subjected to molecular analyses to search for markers of immune response in this population.
Analysis of biomarker data will include correlations with clinical phenotype and tumor PD-L1 expression.
Characteristics of patients
200 frail and/or elderly patients with metastatic non-small cell lung cancer with no targetable molecular alterations (EGFRwt, EML4ALKtransl-) before 1st-line treatment will be included.
Key inclusion criteria are age ≥70 years and/or CCI >1 and/or ECOG >1, previously untreated NSCLC with no targetable molecular alterations (EGFRwt, EML4ALKtransl-) and the availability of a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (fresh or archival less than three years old or recent) or a minimum of ten unstained slides of tumor sample for biomarker (PD-L1) evaluation. Key exclusion criteria include mixed small cell lung cancer with NSCLC and large-cell lung carcinoma histology and history of another primary active malignancy or active autoimmune disease.
For a full list of inclusion and exclusion criteria see Table 1.
Procedures for stratification
Patients are stratified by the principal investigator or authorized delegate from the study staff according to modified Cancer and Age Research Group (CARG) to receive respectively (10,22):
- Total risk score ≤ 3 → doublet chemotherapy
- Total risk score > 3 → single-agent chemotherapy
The aim is to prevent >50% of standard chemotherapy toxicities (CTCAE grade III/IV). The risk score will be determined according to Table 2.
The subjects must first read, understand, and sign the -approved informed consent form (ICF ) before any study-specific screening procedures are performed. After signing the ICF, completing all screening procedures, and being deemed eligible for entry, subjects will be enrolled in the study. Procedures that are performed prior to the signing of the ICF and are considered standard of care may be used as screening assessments if they fall within the 28-day screening window (in particular tumor stagings).
After the stratification procedure, (modified CARG score) done by the investigator, the investigator will access the randomisation website to assign the participant to the treatment arms. Randomisation is performed using permuted block randomisation with fixed block lengths. Treatment arm allocation (ratio 1:1) will be done following the Standard Operational Procedures of the Institut für Klinische Forschung (IKF, Frankfurt Germany), which is the clinical research organisation of the DURATION trial (CRO). After randomisation the system will immediately confirm the patients allocation to the treatment arms, to receive either four cycles of single agent or doublet chemotherapy or two cycles of single-agent or doublet chemotherapy followed by two cycles of immunotherapy. After four cycles of standard chemotherapy patients receive either follow-up care (arm A and D) or a maintenance therapy with durvalumab for a maximum of two years in the experimental arms B and C. Dose modification and toxicity management is described in detail in the chapter “Treatment plan” of the protocol. Furthermore, detailed information about permitted or prohibited concomitant treatment are obtained in the protocol.
Subject adherence to protocol interventions: No particular methods to improve adherence to trial intervention have been implemented. Due to the nature of the disease under study (advance or metastatic lung cancer), patients are naturally motivated to adhere to the trial intervention. Furthermore, the trial medication is not self-administered by the study subjects but rather investigator administered according to a pre-specified visiting calendar of the trial protocol.
Strategies to achieve target sample size: The DURATION trial was set-up with the clinical trial network of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Each of the 30 participating site was selected by the sponsor based on former and anticipated accrual performance. The accrual rate is monitored on a monthly basis and any shortfall communicated to the CI and the sponsor. Regular newsletters and meetings within the trial network are routine tools to maintain a steady accrual rate. Based on the discretion of the sponsor additional study sites may be included to bolster recruitment.
For each patient enrolled, an electronic case report form (eCRF) must be completed by the principal investigator or authorized delegate from the study staff. This also applies to records for those patients who fail to complete the study. If a patient withdraws from the study, the reason must be noted in the eCRF. Subjects who are permanently discontinued from the study medication will be followed for safety unless consent is withdrawn or the subject is lost to follow-up or enrolled in another clinical study. All subjects will be followed for survival. Subjects who decline to return to the site for evaluations will be offered follow-up by phone as an alternative.
Treatment emergent adverse events (AEs) according to common terminology criteria for adverse events (CTCAE) version 4.03 will be recorded in the eCRF using a recognized medical term or diagnosis that accurately reflects the event. Adverse events will be assessed by the investigator for severity, relationship to the investigational product, possible etiologies, and whether the event meets criteria of a serious adverse event (SAE) and therefore requires immediate notification to the CRO. AEs and SAEs will be recorded during the entire study duration, including the regular 30 day safety follow-up period after the end-of-treatment (EOT) visit. Subsequently, subjects will be followed for ongoing study treatment-related adverse events until resolved, return to baseline or deemed irreversible, until lost to follow-up, or withdrawal of study consent. Non-serious adverse events are recorded from time of signed informed consent until 30 days after last dose of the investigational medicinal product (IMP). Serious adverse events are recorded from time of signed informed consent until 90 days after last dose of IMP. Adverse events of special interest (non-serious and serious AESI) are recorded from time of signed informed consent until 90 days after last dose of IMP. The investigator is responsible for ensuring that all adverse events observed by the investigator or reported by patient are properly captured in the patients’ medical records. During the course of the study all AEs and SAEs should be proactively followed up for each subject. Every effort should be made to obtain a resolution for all events, even if the events continue after discontinuation/study completion.
A data safety monitoring board (DSMB) is installed to monitor trial conduct. The primary objective of the DSMB is to monitor the safety of the intervention of the clinical study according to the protocol. The DSMB will evaluate the safety of the study intervention and will propose changes, termination or continuation of the trial to the sponsor and the Coordinating Investigator. It will consist of two experienced thoracic oncologists. The first interim safety assessment will be conducted after the first 20 subjects have been treated with at least two cycles of durvalumab. Thereafter, yearly assessments, synchronized with the annual safety reports, will be performed. Details are provided in the protocol referring to the DSMB Charter.
Monitoring/audits: The CRO must provide a trained monitor to assist the investigators in conducting the clinical study. The monitor has the responsibility of reviewing the ongoing study with the investigators to verify adherence to the protocol and to deal with any problems that arise. The study monitor will review the eCRF data for completeness and accuracy during the monitoring visits. The study monitor will point out any discrepancies between source data and the data captured in the eCRF. The monitor will issue electronic queries to site staff to initiate discrepancy resolution. Discrepancies which require eCRF data corrections have to be re-solved by authorized site personnel by answering these monitoring queries. The frequency of on-site visits will depend on the number of recruited patients and results of prior monitorings (risk-adapted monitoring). The monitor must be given access to subject medical records and other study-related records needed to verify the entries in the eCRF. The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the course of these monitoring visits, including delays in completing case report forms, are resolved. The Investigator has to ensure that all data required according to this protocol will be entered promptly in the eCRF.
Collection of Safety data / harms: It is the responsibility of the investigators to document all adverse events occurring during the study in the patients’ medical files and the eCRF. Any serious adverse event (SAE), AE of special interest, overdose of IMP and pregnancies must be reported immediately (within 24 hours) to the sponsor. The Sponsor and the CRO will ensure compliance with all regulatory reporting requirements including the notification of the appropriate Ethics Committees, Competent Authority and participating investigators of all serious adverse events occurring at the sites in accordance with national law, ICH Good Clinical Practice and European / EMA requirements.
A Sponsor representative (e.g. CRO) will medically review all SAE reports and perform the expectedness assessment.
Every SAE, being assessed by either the investigator or the Sponsor as suspected to be related to IMP und assessed as being either unexpected or unexpected with regard to outcome or severity of the event will be reported by the Sponsor as SUSAR to the competent authority, responsible ethics committee and investigators of the trial in line with the national regulations in effect (German drug law [AMG] and GCP-V § 13).
Data Management and data quality assurance:
Accurate and reliable data collection will be assured by verification and cross–check of the eCRF against the investigator’s records by the study monitor (source document verification), and the maintenance of a drug–dispensing log by the investigator. Data for this study will be recorded via eCRF by the site from the source documents. Data are reviewed and checked for omissions, apparent errors, and values requiring further clarifications using computerized (automatic) and/or manual procedures. Data queries requiring clarification are communicated to the site for resolution via the CRO. Only authorized personnel will make corrections to the clinical database and an audit trail will document all corrections.
Information flow: Protocol amendments are submitted to the competent authorities and ethics committees for approval according to local legislation. Only after regulatory approval changes to the protocol are communicated to all sites via Mail or newsletter. Important safety information (e.g. SUSARS) are communicated directly to the participating investigator in parallel to reporting such information to the competent authorities.
An overview of all study procedures is presented in table 3.
Treatment arms A and D: standard of care single agent or doublet chemotherapy
Arm A: nab-paclitaxel 100mg/m² on days d1 and d8 and carboplatin area under the curve (AUC) 5 on day 1, every 3 weeks up to four cycles.
Arm D: Gemcitabine 1000mg/m² on days d1 and d8, given every 3 weeks, or vinorelbine 30mg/m² on days d1 and d8 every 3 weeks up to four cycles.
Treatment arms B and C: 2 cycles of single agent or doublet chemotherapy followed by durvalumab
Arm B: Two cycles of nab-paclitaxel 100 mg/m² on days d1 and d8 and carboplatin area under the curve (AUC) 5 on day 1, every 3 weeks followed by durvalumab 1125 mg every 3 weeks for two cycles followed by maintenance with durvalumab 1500 mg every 4 weeks.
Arm C: Two cycles of gemcitabine 1000 mg/m² on days d1 and d8, given every 3 weeks or vinorelbine 30 mg/m² on days d1 and d8 every 3 weeks up to four cycles followed by durvalumab 1125 mg every 3 weeks for two cycles followed by maintenance with durvalumab 1500 mg every 4 weeks.
Tissue and blood collection for exploratory endpoints
For each patient a FFPE tumor tissue block (archival or recent) or a minimum of ten unstained slides of tumor sample (2-3 µm sections; slices must be recent and collected on slides provided by the sponsor) must be available for biomarker (PD-L1) evaluation as stated in the inclusion criteria. Biopsy should be excisional, incisional or core-needle. Fine-needle aspiration is insufficient. Tumor PD-L1 expression is measured by an immunohistochemistry assay using SP263 antibody. If a re-biopsy upon tumor progression under study treatment is performed, submission of this tumor material is highly valued.
Participation of patients in the biomarker program is voluntary and must be documented in the informed consent form. The time points for blood sampling are before start of any treatment at baseline and after two cycles of chemotherapy, as well as after 20 weeks of study participation for all patients with stable disease or tumor regression and at the time point of detection of tumor growth in patients with disease progression. In arms B and C, blood is additionally collected after the first cycle of durvalumab.
The primary endpoint is the rate of treatment related grade III/IV adverse events (CTCAE V4.03). It will be calculated taking into account patients who have received at least one dose of study medication.
Secondary endpoints will be:
- Overall response rate (ORR) according to RECIST 1.1 criteria
- Progression-free survival (PFS) will be calculated from the date of subject randomization until the date of confirmed PD or death from any cause; if no event is observed (e.g. lost to follow-up) PFS is censored at the time of last tumor assessment
- Overall survival (OS) will be calculated from the date of subject randomization until the date of death from any cause; if no event is observed (e.g. lost to follow-up) OS is censored at the day of last subject contact
- AEs/SAEs according to CTCAE 4.03
- Health-related quality of life (HR-QoL) assessment using Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire, a standard instrument to determine QoL including lung specific domains (23)
Exploratory analysis on tissue samples
Patients will provide a tumor tissue sample at screening to determine PD-L1 expression level. This assessment will be centralized and performed by an immunohistochemistry assay using SP263 antibody. The results will be used to correlate PD-L1 staining intensity (proportion of positive tumor and immune cells) with durvalumab efficacy.
Exploratory analysis on blood samples
Blood samples that are collected at different time points will be used to characterize the immune response and investigate biological processes before, during and after the administration of the treatment. Flow cytometric (FCM) analysis will be used to characterize the immune response and the biological processes before, during and after the administration of the treatment. Whole blood samples will be analysed with this modality with respect to changes in T-cell composition. Abundances of immunostimulatory cytokines will be quantified by measuring serum pro- and anti-inflammatory cytokines. Analysis of mutational load on cfDNA will be performed.
The primary safety endpoint for the study is the occurrence of CTCAE grade III/IV toxicities assessed from the first dose to 90 days after the last dose of durvalumab. This is also the primary study endpoint on which the sample size calculation is based. According to the results presented at ASCO 2015 by Rizvi it is assumed that the probability for a CTC grade III/IV toxicity for patients from the pooled experimental arms B+C receiving durvalumab amounts to PB+C=0.18 (24). Based on reported data of selected treatment related adverse events (combination chemotherapy nab-paclitaxel/carboplatin (25), mono-chemotherapy gemcitabine/vinorelbine (7)) it is furthermore assumed that the rate of patients with a CTC grade III/IV toxicity in the pooled control arms A+D receiving chemotherapy only amounts to PA+D=0.35. With the planned number of patients of N=200, the assumed difference between these two groups can be detected using a Chi-square test at a two-sided significance level of α=10% with a probability of 1-β=0.80, also taking into account a dropout rate of 15%. Sample size calculation was performed using ADDPLAN v6.1.
It should be noted that the study is not powered to detect significant differences with regard to the efficacy endpoints, since its primary aim is to assess safety and tolerability. Hence, no confirmatory evidence can be drawn from the efficacy evaluation. Accordingly, all p-values for efficacy outcomes are only to be interpreted descriptively and no adjustment for multiple testing will be done.
The null hypothesis for the primary (safety) endpoint of the trial is defined as H0: PB+C = PA+D (i.e., the rate of patients with a CTC grade III/IV toxicity is equal in the pooled experimental arms B+C and the pooled control arms A+D), which is tested against its alternative H1: PB+C ≠ PA+D (i.e., there is a difference between the pooled experimental arms B+C and the pooled control arms A+D with regard to the rate of patients with a CTC grade III/IV toxicity). These hypotheses will be assessed at a two-sided significance level of α=0.1 using a Mantel-Haenszel Chi-square test adjusting for the stratum “adopted combination/not prone to combination”. Missing data for the primary outcome variable will be replaced by using multiple imputation (26). The analysis of the primary endpoint will be based on the Safety Population comprising all patients enrolled who received at least one dose of study medication. Secondary endpoints will be analyzed descriptively. The analysis of PFS will be performed analogously to the analysis of OS by calculating one-year and two-year rates, median times per group, conducting a stratified log rank test, calculating Kaplan Meier curves and estimating the hazard ratio using a Cox regression adjusting for the stratum “adopted combination/not prone to combination”. Other secondary endpoints will be analyzed descriptively by tabulating the measures of the empirical distributions. Subgroup analyses according to PD-L1 expression will be performed. A detailed methodology for the statistical analysis will be described in the statistical analysis plan (SAP), which will be finalized before data base lock. Statistical analysis will be done using SAS v9.4 or higher (SAS Institute, Cary, NC).