Customized Neoadjuvant Versus Standard Chemotherapy in NSCL Patients With Resectable Stage IIIA (N2)Disease

NCT ID: NCT01784549

Last Updated: 2014-11-25

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 168 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2015-12-31

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.

Conditions

Non Small Cell Lung Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cisplatin Docetaxel

\- Cisplatin + Docetaxel day 1 q 21 days for 3 cycles

Group Type: ACTIVE_COMPARATOR

Cisplatin Docetaxel Gefitinib Pemetrexed Vinorelbine Gemcitabine

Intervention Type: DRUG

Gefitinib Pemetrexed Vinorelbine Gemcitabine

• Gefitinib day for 8 wks;
• Pemetrexed day 1 q 21 days for 3 cycles;
• Docetaxel day 1 + Vinorelbine days 1,8 q 21 days for 3 cycles;
• Docetaxel days 1,8 + Gemcitabine days 1,8 q 21 days for 3 cycles;
• Cisplatin + Docetaxel day 1 q 21 days for 3 cycles;
• Cisplatin day 1+ Gemcitabine days 1,8 q 21 days for 3 cycles;

Group Type: EXPERIMENTAL

Cisplatin Docetaxel Gefitinib Pemetrexed Vinorelbine Gemcitabine

Intervention Type: DRUG

Interventions

Cisplatin Docetaxel Gefitinib Pemetrexed Vinorelbine Gemcitabine

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Azienda Sanitaria Locale di Cagliari

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera San Gerardo di Monza

OTHER

Sponsor Role: collaborator

Ospedale Santa Croce-Carle Cuneo

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera S. Maria della Misericordia

OTHER

Sponsor Role: collaborator

Istituto Tumori Giovanni Paolo II, BARI

UNKNOWN

Sponsor Role: collaborator

Azienda Ospedaliera dei Colli Monaldi-Cotugno-CTO, Napoli

UNKNOWN

Sponsor Role: collaborator

Azienda Ospedaliera Santa Maria Degli Angeli

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera San Camillo Forlanini

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera San Giovanni Battista

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera Universitaria Integrata Verona

OTHER

Sponsor Role: collaborator

Azienda Sanitaria Locale n.2 Savonese

OTHER

Sponsor Role: collaborator

ASL TO4, Chivasso

UNKNOWN

Sponsor Role: collaborator

Azienda Provinciale per i Servizi Sanitari, Provincia Autonoma di Trento

OTHER

Sponsor Role: collaborator

Istituto Clinico Humanitas

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera "Sant'Andrea"

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera, Ospedale Civile di Legnano

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera Spedali Riuniti di Livorno, Livorno

UNKNOWN

Sponsor Role: collaborator

IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

OTHER

Sponsor Role: lead

Responsible Party

Francesco Grossi

Chief, Lung Cancer Unit

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Francesco Grossi, MD

Role: PRINCIPAL_INVESTIGATOR

IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

Locations

IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro

Genoa, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Francesco Grossi, MD

Role: CONTACT

fg1965@libero.it

+393355255484

Facility Contacts

Francesco Grossi, MD

Role: primary

fg1965@libero.it

+393355255484

Other Identifiers

2011-005267-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CONTEST TRIAL RF-2009-1530324

Identifier Type: -

Identifier Source: org_study_id