Non Small Cell Lung Cancer
Conditions
Keywords
NSCL, biomarkers, Customized Neoadjuvant Therapy
Brief summary
* The investigators hypothesized that NSCL patients receiving therapy based on their baseline tumor markers levels would attain higher response rates than patients in the control arm receiving non customized therapy. * patients with stage IIIA(N2) NSCLC will be randomized in a 2:1 ratio to customized therapy based on biomarkers status (ERCC1, RRM1, TS and EGFR mutation) vs standard chemotherapy. * The primary objective of this multicenter trial is to compare pathological complete response of all subjects randomized, by treatment arm. * Secondary objectives are to compare all randomized subjects by treatment arm for: response rate, disease-free survival, overall survival, one, two and three year survival and safety profile. The study is expected to demonstrate both the feasibility of this approach and the logistic problems associated with a biomarker-driven therapeutic strategy in NSCLC.
Detailed description
\- Subjects will be stratified by histology and biological markers (ERCC1, RRM1, TS, EGFR mutation). Randomization will be centralized at the coordinating centre site. Patients will receive chemotherapy with cisplatin + docetaxel or customized therapy for 3 cycles (60 days with gefitinib) before surgery. Every 4 months for 3 years and then every 6 months for 2 years following surgery, subjects will be assessed by the investigator for adverse events related to study drug, documentation of post study therapies received, DFS, and survival. \- Periodic evaluations of the trial data will be conducted by an independent data monitoring committee to ensure subject safety and the validity and scientific merit of the study. Assuming that the study is not stopped at the planned futility analyses or for safety reasons, the final analysis will take place after the targeted number of events (pathological complete response) is reached, which is estimated to take place 24 months post study initiation. \- The pathological complete response (pCR)in the two groups will be computed in the ITT populations and compared by means of the chi-square test without continuity correction. For exploratory purposes, a multivariate logistic regression model will be fitted to the data, with the pCR as the response variable and treatment (standard/ experimental) and histo/molecular subgroup as covariate. The heterogeneity of the relative efficacy of the tailored approach in the various subgroups (=subgroup analysis) will be evaluated by including in the model the appropriate set of treatment-by-subgroup interaction terms, using the standard likelihood ratio test. Time-to-event analyses (DFS and OS) will use standard Kaplan-Meier estimators (with the Log-rank test) and semi-parametric PH regression models. Safety will be summarized based on adverse events, vital signs and laboratory assessments. A group sequential design is used to compare the Overall Survival in the two study arms.
Interventions
DRUGCisplatin Docetaxel Gefitinib Pemetrexed Vinorelbine Gemcitabine
Sponsors
Azienda Sanitaria Locale di Cagliari
Azienda Ospedaliera San Gerardo di Monza
Ospedale Santa Croce-Carle Cuneo
Azienda Ospedaliera S. Maria della Misericordia
Istituto Tumori Giovanni Paolo II, BARI
Azienda Ospedaliera dei Colli Monaldi-Cotugno-CTO, Napoli
Azienda Ospedaliera Santa Maria Degli Angeli
Azienda Ospedaliera San Camillo Forlanini
Azienda Ospedaliera San Giovanni Battista
Azienda Ospedaliera Universitaria Integrata Verona
Azienda Sanitaria Locale n.2 Savonese
ASL TO4, Chivasso
Azienda Provinciale per i Servizi Sanitari, Provincia Autonoma di Trento
Istituto Clinico Humanitas
Azienda Ospedaliera Sant'Andrea
Azienda Ospedaliera, Ospedale Civile di Legnano
Azienda Ospedaliera Spedali Riuniti di Livorno, Livorno
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of a signed and dated written informed consent document prior to any study specific procedures. * Age ≥18 years, male or female. * Histologically confirmed NSCLC. * Specimen tumor tissue obtained from mediastinoscopy * ECOG Performance status (PS) 0-1. * Stage IIIA(N2) patients with technical operable disease limited to T1a,b, T2a,b N2 M0; T3 (\>7 cm) N2 M0. * Medically fit for resection by lobectomy or pneumonectomy. * Radiologically measurable disease (RECIST v1.1 criteria). * Prior surgery for NSCLC if resected ≥5 years. * No prior chemotherapy, targeted-therapy, investigational therapy or radiation for NSCLC. * No uncontrolled medical problems. * No superior vena cava syndrome. * Peripheral neuropathy must be ≤ grade 1. * Acceptable hematologic and chemistry parameters. * Creatinine clearance \>50 ml/min. * Female patients or their partners must be surgically sterile or be postmenopausal, or agree to use effective contraception while in trial treatment and for 3 months thereafter. * Female patients with reproductive potential must have a negative pregnancy test (serum or urine) within 72 hours prior to starting treatment. * Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures including patient reported measures.
Exclusion criteria
* Any evidence of mixed histology including elements of small cell or carcinoid lung cancer. * Stage IIIA patients limited to T3 N1 M0; T3 (invasion) N2 M0; T4 N0, N1 M0. * Any clinically significant GI abnormalities, which may impair intake, transit or absorption of gefitinib, such as the inability to take oral medication. * Current enrollment in another therapeutic clinical trial. * Any psychiatric or cognitive disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this study. * Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease * Pre-existing idiopathic pulmonary fibrosis evidence by computerized tomography (CT) scan at baseline. * Uncontrolled or significant CV disease, including: myocardial infarction within 12 months; uncontrolled angina within 6 months; congestive heart failure within 6 months; diagnosed or suspected congenital long QT syndrome; * Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); * Prolonged QTc interval on pre entry ECG. * Any history of second or third degree heart block (may be eligible if currently have a pacemaker); * Heart rate \<50/minute on baseline ECG; * Uncontrolled hypertension. * Evidence of prior malignancy (other than non melanoma skin cancer or in situ cervical cancer, or localized and presumed cured prostate cancer with PSA \< ULN) within the last 3 years. * Other severe acute or chronic medical condition that may increase the risk associated with trial participation or may interfere with the interpretation of trial results and, in the judgment of the investigator. * Patients in whom corticosteroid premedication was contraindicated. * HIV-positive patients on active treatment. * Medications are prohibited at baseline and prior to randomization if they affect the pharmacokinetics of gefitinib, cisplatin, docetaxel, gemcitabine, vinorelbine and pemetrexed or if they are mainly metabolized by CYP3A4. * Patients who are otherwise eligible can be enrolled only if drug substitution is performed with acceptable clinical outcome prior to enrollment: known severe hypersensitivity to gefitinib or other chemotherapeutic agents or any of the excipients of the products. * Pregnancy or breast-feeding.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pathologic Complete Response | 30 days |
Secondary
| Measure | Time frame |
|---|---|
| Overall Survival (OS) | at 1, 2, and 5 years |
| Disease-Free Survival (DFS) | at 1, 2, and 5 years |
| Overall Response (OR) | at 1, 2, and 5 years |
Countries
Italy
Contacts
Primary ContactFrancesco Grossi, MD
Outcome results
None listed