E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
locally advanced stage IIIA/B NSCLC |
CNMP localmente avanzado en estadio IIIA/B |
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E.1.1.1 | Medical condition in easily understood language |
A type of lung cancer called "non small cell lung cancer (NSCLC)" that has spread locally in the area of the lung, but not to distant organs and tissues |
Tipo de cáncer de pulmón llamado " cáncer de pulmón de células no pequeñas (CNMP) " que se ha extendido a nivel local en la zona del pulmón , pero no a los órganos y tejidos distantes |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029520 |
E.1.2 | Term | Non-small cell lung cancer stage IIIA |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the feasibility of the administration of nivolumab after concurrent or sequential chemotherapy and radiotherapy for stage III NSCLC, as defined by the rate of grade ?3 pneumonitis (CTCAE V4.0) 6 months post-radiotherapy |
Evaluación de la factibilidad de la administración de nivolumab tras la quimioterapia y radioterapia concomitantes o secuenciales del CNMP en estadio III, definida por la tasa de neumonitis de grado >3 (V4.0 de CTCAE) a los 6 meses de la radioterapia. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate secondary measures of clinical efficacy including time to first grade ?3 pneumonitis (TFP3), progression-free survival (PFS), objective response rate (ORR), time to treatment failure (TTF) and overall survival (OS).
- To assess the safety and the tolerability of the Treatment.Please enter information in English and add any other language that is applicable |
Evaluar las medidas secundarias clínicas: ? Tiempo hasta la neumonitis inicial ? Supervivencia sin progresión ? Tasa objetiva de respuesta según RECIST, v1.1 ? Tiempo hasta el fracaso terapéutico ? Supervivencia global
Evaluar la seguridad y la tolerabilidad de la tratamiento. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically or cytologically confirmed non small cell lung cancer - Locally advanced stage IIIA or III B (T0-3 N2-3 or T4N0-3 M0) NSCLC, according to 7th TNM classification. - Nodal status N2 or N3 needs to be proven (by biopsy, EBUS, mediastinoscopy or thoracoscopy). - Whole body FDG-PET CT, if feasible including a contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals) - brain MRI (preferred) or high-quality brain CT with intravenous contrast at the time of staging mandatory within 28 days before enrolment. - Measurable disease (according to RECIST v1.1 criteria) - Age ? 18 years - Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 (see below*) - Life expectancy > 3 months - Adequate haematological function: - WBC ? 2000/?L - haemoglobin ? 9 g/dL - neutrophil count ? 1×109/L - platelet count ? 100 × 109/L - Adequate liver function: - Total bilirubin ? 1.5 x ULN (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dl) - ALT ?3 × ULN - alkaline phosphatase ? 5 x ULN. - Adequate renal function: Calculated creatinine clearance ? 30 ml/min (according to Cockroft-Gault) - Pulmonary function FEV1 of 1.0 l or > 40% predicted value and DLCO > 30% predicted value - Patient capable of proper therapeutic compliance, and accessible to correct follow-up. - Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before beginning chemo-radiotherapy (the test needs to be repeated within 24 hours before the start of nivolumab treatment). - Written Informed Consent (IC) for trial treatment must be signed and dated by the patient and the investigator prior to any trial-related evalutation and/or intervention. |
- Cáncer no microcítico de pulmón (CNMP) localmente avanzado, en estadio IIIA o III B (T0-3 N2-3 o T4 N0-3 M0) confirmado por el estudio histológico o citológico, con arreglo a la 7ª clasificación TNM. - Estadio ganglionar N2 o N3 pendiente de confirmación (mediante biopsia, ecografía endobronquial, mediastinoscopia o toracoscopia) - Enfermedad mensurable según RECIST, v1.1 - Categoría funcional ECOG 0-1 - ALT ? 3 x LSN - Función renal adecuada, con un aclaramiento de creatinina calculado ? 30 ml/min (según la fórmula de Cockroft-Gault) |
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E.4 | Principal exclusion criteria |
- Patient with mixed small-cell and non-small-cell histologic features - Patient with pleural or pericardial effusions proven to be malignant - Prior chemotherapy, radiotherapy or molecular targeted therapy for NSCLC - Patient who has an active, known or suspected autoimmune disease. Patients are permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. - Patient who has had in the past 3 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast. - Patient with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient?s capacity to participate in the study. - Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, antifungal therapy. - Known or suspected hypersensitivity to nivolumab or any of its excipients - History of severe hypersensitivity reaction to any monoclonal antibody - Substance abuse, medical, psychological or social conditions that may interfere with the patient?s participation in the study or evaluation of the study results. - Established pathological diagnosis of underlying interstitial lung disease or pulmonary fibrosis - Women who are pregnant or in the period of lactation - Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the study treatment and for a period of at least 12 months following the last administration of trial drugs. - Patients with any concurrent anticancer systemic therapy - HIV, active Hepatitis B or Hepatitis C infection - Previous radiotherapy to the thorax (prior to inclusion), including RT for breast cancer - Planned radiotherapy to lung of mean dose > 20 Gy or V20 > 35 % - Patient who received treatment with an investigational drug agent during the 3 weeks before enrolment in the trial - Metastatic disease (brain MRI or high-quality CT with intravenous contrast at the time of staging mandatory) - Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways |
- Enfermedad metastásica (se exigirán PET-TAC y RM cerebral (preferida) o TC cerebral de alta calidad con contraste por vía intravenosa en el momento de la estadificación) - Radioterapia previa de tórax, incluida la radioterapia por cáncer de mama - Quimiorradioterapia, radioterapia o tratamiento molecular dirigido previos contra el CNMP - Enfermedad autoinmune activa, conocida o sospechada |
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E.5 End points |
E.5.1 | Primary end point(s) |
Grade ?3 pneumonitis (CTCAE V4.0) |
neumonitis de grado >3 (V4.0 de CTCAE) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
It will be used as the primary endpoint for all patients followed for at least 6 months from end of radiotherapy. |
Se usa como el criterio principal de valoración para todos los pacientes seguidos durante al menos 6 meses a partir de final de la radioterapia . |
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E.5.2 | Secondary end point(s) |
- Time to first grade ?3 pneumonitis (TFP*) - Progression-free survival (PFS) by RECIST v1.1 - Objective Response (OR) determined by RECIST v1.1 - Time to treatment failure (TTF) - Overall survival (OS) - Adverse events graded according to CTCAE V4.0 |
- Tiempo hasta la neumonitis inicial (TNI) - Supervivencia sin progresión (SSP) - Tasa objetiva de respuesta según RECIST, v1.1 (TOR) - Tiempo hasta el fracaso terapéutico (TFT) - Supervivencia global (SG) - Acontecimientos adversos graduados según V4.0 de CTCAE |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-TFP3 is defined as the time from the date of enrolment until first documented pneumonitis of grade ? 3. -PFS:It is defined as the time from the date of enrolment until documented progression or death, if progression is not documented. - OR:Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrolment to termination of trial Treatment or will be evaluated both from date of enrolment and from date of first nivolumab dose. - TTF:Time to treatment failure is defined as time from enrolment to discontinuation of treatment for any reason, including disease progression, treatment toxicity,and death. - OS:Defined as time from the date of enrolment until death from any cause. - AEs: during complete trial duration |
- TNI: periodo desde la fecha de reclutamiento hasta la primera neumonitis documentada de grado ? 3 . - SSP: periodo desde la fecha de reclut. hasta la progresión documentada o la muerte, si la progresión no está documentada . - TOR: mejor respuesta global ( RC o RP ) en todos los puntos de tiempo de evaluación durante el período de reclutamiento para la finalización del tratamiento de prueba o será evaluado tanto desde la fecha de reclutamiento y a fecha de la 1a dosis de Nivolumab . - TFT: periodo de reclutamiento a la interrupción del tratamiento por cualquier razón, incluyendo progresión de la enfermedad , la toxicidad del tratamiento, y la muerte. - SG: desde la fecha de reclutamiento hasta la muerte por cualquier causa. - AA Graduados: Durante toda la duración del ensayo. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Germany |
Netherlands |
Spain |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Patient accrual is expected to be completed within 12 months incl.a run-in-period of 6 months. Treatment and follow-up is expected to extend the time of evaluation of the primary endpoint to 18 months. Follow-up will continue until 2 years from start of nivolumab treatment of the last recruited patient. The trial will end with the preparation of the final report,scheduled at 4 years after the inclusion of the first patient. |
Se espera que el reclutamiento de pacientes sea completado dentro de 12 meses. Se espera que el periodo de tratamiento y el de seguimiento extiendan el tiempo de evaluación de la variable principal a 18 meses. El seguimiento continuará hasta 2 años a partir del inicio del tratamiento nivolumab del último paciente reclutado . El ensayo concluirá con la elaboración del informe final , programado a los 4 años después de la inclusión del primer paciente . |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |