E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent or refractory rhabdomyosarcoma |
Rabdomiosarcoma recurrente o refractario |
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E.1.1.1 | Medical condition in easily understood language |
Rhabdomyosarcoma |
Rabdomiosarcoma |
|
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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039027 |
E.1.2 | Term | Rhabdomyosarcoma recurrent |
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 efficacy of the combination of temozolomide with vincristine and irinotecan in children and adult patients with refractory or relapsed rhabdomyosarcoma as assessed by confirmed objective tumor response |
Evaluar la eficacia de la combinación de temozolomida con vincristina e irinotecan en niños y adultos con rabdomiosarcoma recidivado o refractario mediante el análisis de la respuesta del tumor. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety, tolerability and efficacy of VIT and VI alone as assessed by: duration of response, time to tumor progression, time to treatment failure, overall survival and adverse event profile Ancillary (optional): - To correlate pharmacogenetic profiles from 384 SNP including UGT1A1, ABCB1, MGMT and from a specific genetic analysis for response and toxicity of VIT and VI |
- Evaluar la seguridad y tolerancia de VIT y VI mediante el análisis de: duración de la respuesta, tiempo hasta la progresión, tiempo hasta el fracaso del tratamiento, supervivencia global y perfil de efectos adversos. Subordinado (opcional): - Correlacionar los perfiles farmacogenómicos de 384 SNPs que incluyen UGT1A1, ABCB1, MGMT con la respuesta y toxicidad de VIT y VI. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
TUMOR CHARACTERISTICS : ? Histologically or cytologically confirmed diagnosis of rhabdomyosarcoma (RMS) (new biopsy recommended) ? Relapsed or refractory disease which has failed standard treatment approaches ? Patients must have measurable disease defined as lesions that can be measured in 3 dimensions by medical imaging techniques such as CT or MRI. Ascites, pleural fluid, bone marrow disease and lesions seen on Tc scintigraphy or PET scan only are not considered measurable for these patients PATIENT CHARACTERISTICS : ? Age > 6 months and < or = 50 years ? Karnofsky performance status (PS) (for patients > 12 years of age) OR Lansky Play Score for patients ? 12 years of age) 0-100% ? Life expectancy ? 12 weeks ? Adequate bone marrow function : Absolute neutrophil count ? 1000/mm3, Platelet count ? 100,000/mm3 (transfusion independent), Hemoglobin ? 8.5 g/dl (transfusion allowed) ? Adequate renal function : Serum creatinine < 1.5 X ULN for age. If serum creatinine > 1.5 ULN, creatinine clearance (or radioisotope GFR) must be >70 ml/min/1.73 m² ? Adequate hepatic function : Total bilirubin ? 1.5 times upper limit of normal (ULN) for age, except if the patient is known to have Gilbert?s syndrome. ALT and AST < 2.5 times ULN for age ? Negative pregnancy test in females with childbearing potential ? Fertile patients must use effective contraception ? No active > grade 2 diarrhea or uncontrolled infection ? No other malignancy, including secondary malignancy ? Patient affiliated with a health insurance system. Applicable for French patients only ? Written informed consent of patient and/or parents/guardians
PRIOR or CONCURRENT THERAPY : ? More than 3 weeks since prior radiation therapy to the site of any progressive lesion that will be identified as a target lesion to measure tumor response ? At least 3 weeks since prior myelosuppressive therapy (6 weeks for nitrosourea. 2 weeks for vincristine, vinblastine, vinorelbine or low dose cyclophosphamide) ? No concurrent enzyme-inducing anticonvulsants (EIAC), including phenytoin, phenobarbital or carbamazepine ? No concurrent administration of any of the following: rifampicin, voriconazole, itraconazole, ketoconazole, aprepitant, St John?s Wort ? No prior irinotecan or temozolomide administration ? Prior vincristine administration allowed ? Concurrent palliative radiation therapy to sites allowed other than the main measurable target ? Prior allo- or autologous SCT allowed |
CARACTERISTICAS DEL TUMOR: ? Rabdomiosarcoma confirmado histológica o citológicamente (se recomienda nueva biopsia) ? Enfermedad refractaria o recaída que ha fracasado con el tratamiento estándar ? Los pacientes deben tener enfermedad medible definida como lesiones susceptibles de ser medidas en 3 dimensiones mediante técnicas de imagen como TAC o RM. La ascitis, el derrame pleural, la infiltración de médula ósea y las lesiones visibles solamente en la gammagrafía con Tecnecio o en la TEP no se consideran lesiones medibles CARACTERISTICAS DE LOS PACIENTES: ? Edad > 6 meses y ? 50 años ? Karnofsky 70-100% (para pacientes > 12 años de edad) o Lansky 70-100% (para pacientes ? 12 años de edad) ? Expectativa de vida ? 12 semanas ? Función de medula ósea adecuada: o Neutrófilos ? 1000/mm3 o Plaquetas ? 100,000/mm3 (sin transfusión) o Hemoglobina ? 8.5 mg/dl (se permite transfusión) ? Función renal adecuada: o Creatinina sérica < 1.5 X límite normal superior (LNS) para la edad o Si creatinina sérica > 1.5 LNS, el aclaramiento de creatinina (o el filtrado glomerular isotópico) debe ser >70 ml/min/1.73 m²
? Función hepatica adecuada: o Bilirrubina total ? 1.5 LNS para la edad o ALT < 2.5 LNS para la edad ? Test de embarazo negativo en mujeres en edad fértil ? Los pacientes fértiles deben usar contracepción efectiva ? No diarrea > grado 2 o infección no controlada ? No otras neoplasias, incluidas neoplasias secundarias ? Consentimiento informado del paciente y/o padres o tutores TRATAMIENTO PREVIO O CONCOMITANTE: ? Al menos 3 semanas desde la administración de radioterapia en la localización de cualquier lesión progresiva que pueda ser identificada como lesion diana para medir la respuesta tumoral ? Al menos 3 semanas desde la administración previa de tratamientos mielosupresores (6 semanas para nitrosourea, 2 semanas para vincristina, vinblastina, vinorelbina o ciclofosfamida a dosis bajas) ? No uso concomitante de anticonvulsivantes inductores enzimáticos incluyendo fenitoina, fenobarbital o carbamazepina ? No uso concomitante de ninguno de los siguientes fármacos: rifampicina, voriconazol, itraconazol, ketoconazol, aprepitant ? No administración previa de irinotecan o temozolomida ? Se permite la administración previa de vincristina ? Se permite la irradiación concomitante paliativa de localizaciones que no sean lesiones diana medibles ? Se permite haber recibido transplante autólogo o alogénico de progenitores hematopoyéticos |
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E.4 | Principal exclusion criteria |
? Concomitant anti-cancer treatment ? Pregnancy or breast feeding ? Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption ? Neuromuscular disorders (e.g. Charcot-Marie Tooth disease) ? Uncontrolled intercurrent illness or active infection ? Unavailable for medical follow-up (geographic, social or psychological reasons) |
?No cumplir los criterios de inclusión ? Tratamiento antineoplásico concomitante ? Embarazo o lactancia ? Pacientes con trastornos hereditarios raros como intolerancia a galactosa, malabsorción glucosa-galactosa y déficit de lactasa Lapp ? Enfermedades neuromusculares (p.ej Charcot-Marie-Tooth) ? Enfermedad intercurrente no controlada o infección activa ? Imposibilidad de seguimiento (por razones geográficas, sociales o mentales) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy The primary efficacy endpoint is the objective response (OR), defined as a documented complete (CR) or partial (PR) volume tumor response after two cycles of treatment in each treatment group. Any CR or PR should be confirmed not less than 4 weeks later, except when early local treatment is performed or a second-line treatment is administered before confirmation at 4 weeks. Responses will be assessed by CT or MRI (3D measurements and tumor volume). An external review committee will review all observations to validate response. Continuing response/stable disease should be confirmed every two cycles until tumor progression or study discontinuation. Further assessment may be performed every 3-4 months. |
El criterio de eficacia principal es la respuesta objetiva (RO), definida como respuesta completa (RC) o parcial (RP) del volumen del tumor después de 2 ciclos de tratamiento. Cualquier RC o RP debe ser confirmada no antes de 4 semanas de la administración del tratamiento, excepto cuando se realice cirugía precoz o cuando se administre una segunda línea de tratamiento antes de las 4 semanas. Las respuestas serán evaluadas mediante TAC o RM (mediciones en 3 D y cálculo del volumen tumoral). Un comité externo revisará todas las observaciones para validar la respuesta. La respuesta continuada/enfermedad estable deberá confirmarse cada 2 ciclos hasta la progresión o la interrupción del estudio. Además se efectuará una evaluación mas completa cada 3-4 meses. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 2 cycles of 21 days |
Después de 2 ciclos de 21 días |
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E.5.2 | Secondary end point(s) |
Toxicity The safety profile will be evaluated in each treatment group. Clinical and laboratory toxicities/symptoms will be graded according to NCI-Common Terminology Criteria AE v4.0 (NCI-CTC). Adverse events which are also reported according to the NCI-CTC will be graded as mild, moderate, severe, or life threatening. - Pharmacogenetic profiles from 384 SNP including UGT1A1, ABCB1, MGMT and from a specific genetic analysis will be correlated with response and toxicity of VIT and VI. - The secondary efficacy variables are the duration of response, the time to treatment failure, the time to progressive disease and overall survival in each treatment group. |
- Toxicidad Se evaluará el perfil de seguridad en cada grupo de tratamiento. Las toxicidades clínicas y analíticas se graduarán de acuerdo con los criterios NCI-CTC (AE v4.0) Los acontecimientos adversos que también se reportarán de acuerdo con los criterios NCI-CTC se graduaran en leves, moderados, graves o de peligro vital. - Análisis farmacogenómico (opcional) Se analizarán los perfiles farmacogenómicos de 384 SNPs que incluyen UGT1A1, ABCB1 y MGMT que se correlacionarán con la respuesta y toxicidad de VIT y VI. - Las variables secundarias de eficacia son la duración de la respuesta, el tiempo hasta el fracaso del tratamiento, el tiempo hasta la progresión de la enfermedad y la supervivencia global de cada grupo de tratamiento. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
2 cycles or more |
2 ciclos o más |
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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 | Yes |
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 | Yes |
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 | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
|
last visit of the last subject undergoing the trial |
última visita del último sujeto reclutado |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |