| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Small Cell Lung Cancer |
| Cáncer de pulmón microcítico metastásico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Lung Cancer |
| Cáncer de pulmón metastásico |
|
| 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 | 10059514 |
| E.1.2 | Term | Small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The primary objective of this study is to determine the efficacy of administration of aldoxorubicin compared to topotecan in subjects with metastatic small cell lung cancer (SCLC) who have relapsed or were refractory to prior chemotherapy, as measured by progression-free survival (PFS). |
| El objetivo principal de este estudio es determinar la eficacia de la administración de aldoxorrubicina en comparación con topotecán en pacientes con cáncer de pulmón microcítico metastásico (CPMM) que han sufrido una recidiva o no han respondido a quimioterapia previa, según lo determinado por la supervivencia libre de progresión (SLP). |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to evaluate the efficacy of aldoxorubicin as measured by overall survival (OS), safety of aldoxorubicin compared to topotecan in this population assessed by the frequency and severity of adverse events (AEs), abnormal findings on physical examination, laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram (ECG) results, and weight, as well as disease control rate and tumor response. |
| The secondary objectives of this study are to evaluate the efficacy of aldoxorubicin as measured by overall survival (OS), safety of aldoxorubicin compared to topotecan in this population assessed by the frequency and severity of adverse events (AEs), abnormal findings on physical examination, laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram (ECG) results, and weight, as well as disease control rate and tumor response. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age >=18 years male or female.
2. Histological confirmation of SCLC.
3. Relapsed or refractory to no more than 1 course of a systemic therapy regimen and is incurable
by either surgery or radiation.
4. Capable of providing informed consent and complying with trial procedures.
5. ECOG PS 0-2.
6. Life expectancy >8 weeks.
7. Measurable tumor lesions according to RECIST 1.1 criteria.
8. Women must not be able to become pregnant (e.g. post-menopausal for at least 1 year, surgically sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate contraception includes: oral contraception, implanted contraception, intrauterine device implanted for at least 3 months, or barrier method in conjunction with spermicide.)
9. Males and their female partner(s) of child-bearing potential must use 2 forms of effective contraception (see Inclusion 8 plus condom or vasectomy for males) from the last menstrual period of the female partner during the study treatment and for 6 months after the final dose of study treatment.
10. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening Visit and be non-lactating.
11. Accessibility to the site that ensures the subject will be able to keep all study-related appointments. |
1. Edad >= 18 años, hombres o mujeres.
2. Confirmación histológica de CPMM.
3. Recidivante o refractario a no más de 1 ciclo de régimen de tratamiento sistémico e incurable bien por cirugía o radiación.
4. Capaz de facilitar consentimiento informado y de cumplir con los procedimientos del ensayo.
5. ECOG PS 0-2.
6. Esperanza de vida >8 semanas.
7. Lesiones tumorales mensurables con arreglo a los criterios RECIST 1.1.
8. Las mujeres no deberán estar en situación de poder quedarse embarazadas (por ej. posmenopáusicas durante al menos 1 año, sometidas a esterilización quirúrgica o usuarias de métodos anticonceptivos adecuados) durante la duración del estudio. (Una adecuada anticoncepción incluye: anticoncepción oral, anticoncepción implantada, dispositivo intrauterino implantado durante los 3 meses anteriores como mínimo, o método de barrera unido a espermicida.)
9. Los hombres y sus parejas de sexo femenino con posibilidad de engendrar deberán utilizar 2 formas de anticoncepción efectiva (véase el criterio de inclusión 8 más preservativo o vasectomía para los hombres) desde el último periodo menstrual de la pareja femenina durante el tratamiento del estudio y durante 6 meses después de la dosis final del tratamiento del estudio.
10. Las mujeres con posibilidades de engendrar deberán tener un resultado negativo en la prueba de embarazo en suero u orina en la visita de selección y no estar en periodo de lactancia.
11. Accesibilidad al centro que garantice que el sujeto podrá ser capaz de acudir a todas las citas relacionadas con el estudio. |
|
| E.4 | Principal exclusion criteria |
1. Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin.
2. Prior treatment with topotecan.
3. Palliative surgery and/or radiation treatment < 21 days prior to date of randomization.
4. Exposure to any investigational agent within 30 days of date of randomization.
5. Exposure to any systemic chemotherapy within 21 days of date of randomization.
6. Active (symptomatic) central nervous system (CNS) metastasis.
7. History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix unless documented free of cancer for ?3 years.
8. Laboratory values: Screening serum creatinine >1.5×upper limit of normal (ULN), alanine aminotransferase (ALT) >3×ULN or >5×ULN if liver metastases are present, total bilirubin >2×ULN, absolute neutrophil count (ANC) <1,500/mm3, platelet concentration <100,000/mm3, hemoglobin <9 g/dL, albumin <2 gm/dL.
9. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) guidelines.
10. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V.
11. Baseline QTc >470 msec measured by Fridericia?s formula (QTcF) and/or previous history of QT prolongation while taking other medications. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed.
12. History or signs of active coronary artery disease with angina pectoris within the last 6 months.
13. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) below the institution?s lower limit of predicted normal.
14. Known history of HIV infection.
15. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or antifungals.
16. Treatment with p-glycoprotein inhibitors such as cyclosporine A, elacridar, ketoconazole, ritonavir, saquinavir.
17. Major surgery within 30 days prior to date of randomization.
18. Substance abuse or any condition that might interfere with the subject?s participation in the study or in the evaluation of the study results.
19. Any condition that is unstable and could jeopardize the subject?s participation in the study. |
1. Exposición previa a >375 mg/m2 de doxorrubicina o doxorrubicina liposomial.
2. Tratamiento previo con topotecán.
3. Cirugía paliativa y/o radioterapia < 21 días antes de la fecha de aleatorización.
4. Exposición a un medicamento en investigación durante los 30 días anteriores a la fecha de aleatorización.
5. Exposición a quimioterapia sistémica durante los 21 días anteriores a la fecha de aleatorización.
6. Metástasis activa (sintomática) del sistema nervioso central (SNC).
7. Antecedentes de otros tumores malignos excepto carcinoma basocelular curado, carcinoma cutáneo de células escamosas, melanoma in situ, cáncer de vejiga superficial o carcinoma in situ de cérvix salvo que estuviera documentado sin cáncer durante ?3 años.
8. Valores de laboratorio: Cribado creatinina sérica >1,5×límite superior de la normalidad (LSN), alanina aminotransferasa (ALT) >3×LSN o >5×LSN si existe presencia de metástasis hepáticas, bilirrubina total >2×LSN, recuento absoluto de neutrófilos (RAN) <1,500/mm3, concentración de plaquetas <100,000/mm3, hemoglobina <9 g/dL, albúmina <2 gm/dL.
9. Insuficiencia cardíaca congestiva (ICC) clínicamente manifiesta > clase II según las directrices de la New York Heart Association (NYHA) (Anexo D).
10. Arritmias cardíacas en curso, graves y clínicamente importantes, definidas como la existencia de una arritmia absoluta o arritmias ventriculares clasificadas como Lown III, IV o V (Anexo F).
11. QTc basal >470 msec determinado por la fórmula de Fridericia (QTcF) y/o antecedentes previos de prolongación del intervalo QT durante la toma de otros medicamentos. No está permitido el uso concomitante de medicamentos asociados con una elevada incidencia de la prolongación del intervalo QT.
12. Antecedentes de signos de enfermedad coronaria activa con angina de pecho durante los últimos 6 meses.
13. Disfunción miocárdica grave definida por ECO como fracción de eyección ventricular izquierda absoluta (FEVI) por debajo del límite inferior de lo previsto como normal por la institución.
14. Antecedentes conocidos de infección por VIH.
15. Infección activa grave médicamente importante que requiera tratamiento con antibióticos, antivirales o antifúngicos.
16. Tratamiento con inhibidores de glucoproteína-p tales como ciclosporina A, elacridar, ketoconazol, ritonavir, saquinavir.
17. Cirugía mayor durante los 30 días previos a la fecha de aleatorización.
18. Consumo abusivo de sustancias o cualquier estado que pueda interferir con la participación del sujeto en el estudio o en la evaluación de los resultados de dicho estudio.
19. Cualquier situación que sea inestable y que pueda perjudicar la participación del sujeto en el estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS). |
| Suprevivencia Libre de Progresión (SLP). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of PFS will be carried out approximately 6 months following the completion of enrollment of 132 subjects. PSF at 4 and 6 month
The final analysis of OS will be completed when 110 OS events have occurred.
Tumor response will be monitored at baseline, every 6 weeks from Cycle 1-Day 1 through week 36, and then every 12 weeks until disease progression |
El análisis principal de la SLP se realizará aproximadamente 6 meses después de completar la inclusión de 132 sujetos. Se realizará una evaluación de la SLP a los 4 y a los 6 meses
El análisis final de la SG se completará cuando hayan ocurrido 110 episodios de SG.
Se controlará la respuesta tumoral en la visita inicial, cada 6 seis semanas desde el Ciclo 1- Día 1 hasta la semana 36, y después cada 12 semanas hasta la progresión de la enfermedad. |
|
| E.5.2 | Secondary end point(s) |
1) To evaluate OS in subjects with extensive-stage SCLC who have relapsed or were refractory to no more than 1 chemotherapy regimen.
2) To evaluate the objective ORR (RECIST 1.1 criteria, Study Reference Manual) and disease control rate (ORR + SD at 4 months) in subjects with extensive-stage SCLC who have relapsed or were refractory to 1 chemotherapy regimen as above.
3) To evaluate PFS at 4 and 6 months.
4) To assess investigator-reported quality of life (ECOG PS).
5) To evaluate the treatment-related toxicities in this subject population. |
1) Evaluar la SG en sujetos con CPM en fase muy avanzada que han sufrido recidiva o no han respondido a no más de 1 régimen de quimioterapia.
2) Evaluar la ORR objetiva (criterios RECIST 1.1, Manual de referencia del estudio) y la tasa de control de la enfermedad (ORR + EE a los 4 meses) en sujetos con CPM en fase muy avanzada que han sufrido recidiva o no han respondido a un régimen de 1 quimioterapia como en el punto anterior.
3) Evaluar la SLP a los 4 y a los 6 meses.
4) Evaluar la calidad de vida notificada al investigador (estado funcional ECOG).
5) Evaluar las toxicidades relacionadas con el tratamiento en esta población de pacientes. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1), 2),4),5),over the duration of the study
3), 4 and 6 month |
1), 2),4),5),durante toda la duración del estudio
3), a los 4 y 6 meses |
|
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Hungary |
| Italy |
| Spain |
| United States |
|
| 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
|
| Survival follow-ups will be conducted by telephone for all subjects every 12 weeks from the time a subject either withdraws from treatment or at disease progression until the subject is either lost to follow-up, passes away, withdraws consent, or the Sponsor stops the study. |
| El seguimiento de la supervivencia se realiza por teléfono para todos los sujetos cada 12 semanas desde el momento en que un sujeto se retire de tratamiento, o progrese la enfermedad hasta que o bien se pierda el seguimiento del sujeto, o bien fallezca, o bien retire su consentimiento, o el promotor pare el estudio. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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