| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced solid tumors |
| Tumores solidos avanzados |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 2 Study
• Determine the antitumor activity of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring ALK, ROS1 or NTRK1-3 alterations. |
Estudio Fase 2
• Determinar la actividad antitumoral de repotrectinib en pacientes pediátricos y adultos jóvenes con neoplasias malignas avanzadas o metastásicas con alteraciones de ALK, ROS1 o NTRK1-3. |
|
| E.2.2 | Secondary objectives of the trial |
• Determine the antitumor activity in terms of DOR, overall survival (OS) and progression-free survival (PFS) following treatment with repotrectinib
• Determine intracranial antitumor activity of repotrectinib
• Evaluate the safety and tolerability of repotrectinib at the pediatric RP2D
• Characterize the PK of repotrectinib at the pediatric RP2D |
• Determinar la actividad antitumoral en cuanto a DR, supervivencia global (SG) y supervivencia sin progresión (SSP) tras el tratamiento con repotrectinib
• Determinar la actividad antitumoral intracraneal de repotrectinib
• Evaluar la seguridad y tolerabilidad de repotrectinib en la DRF2 para pacientes pediátricos
• Confirmar la FC de repotrectinib con la DRF2 para pacientes pediátricos |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Phase 2: EU will not participate in Cohort 1.
Cohort 2: Subjects with NTRK+ advanced solid tumors (including primary CNS tumors), TRK TKI-pretreated. Nonresponse, disease progression or intolerability to at least 1 but no more than 2 prior TRK TKIs. Any prior lines are allowed.
Cohort 3: in the EU: (1) subjects with NTRK fusions without centrally confirmed measurable disease but otherwise eligible for Cohort 2, and (2) subjects with ROS1 fusions.
•Documented genetic ALK, ROS1, or NTRK1-3 alteration as identified by local testing in a CLIA laboratory in the US or equivalent.
•For subjects enrolled per tissue-based test, adequate tumor tissue should be sent prior to enrollment to the central lab. If archived tumor tissue is not available, a fresh biopsy should be obtained.
For subjects enrolled by liquid biopsy test; blood samples should be sent prior to enrollment to the central lab.
2.Subjects must have recovered from the acute toxic effects of all previous therapies prior to study enrollment to CTCAE v4.03 criteria ≤grade 1, with the exception of alopecia. Subjects must not have received the therapies indicated below for the specified time period:
•Chemotherapy: Last dose given at least 14 days or 5 half-lives before the start date for repotrectinib.
•Monoclonal antibodies (not including IO therapeutic antibodies): Last dose given at least 21 days prior to the start date for repotrectinib.
•Immunotherapy (eg, IO therapeutic antibodies or tumor vaccine): Subject is eligible after 28 days of completion prior to first dose of repotrectinib. Steroids are not considered immunotherapy.
•Radiation therapy: Subjects must not have received radiation for a minimum of 2 weeks prior to study enrollment. If extensive bone marrow radiation, at least 42 days must have elapsed.
•HSCT: Subjects are eligible 12 weeks after infusion following myeloablative therapy (timed from first day of repotrectinib). Subjects who have received an infusion to support nonmyeloablative therapy (such as 131I MIBG) are eligible at any time as long as they meet the other criteria.
•131I-MIBG therapy: A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of repotrectinib.
•Growth factors: Subjects are eligible 14 days after last dose of long-acting growth factor or 7 days after short-acting growth factor.
•Any investigational agent or anticancer therapy other than chemotherapy and not otherwise noted: Not within 2 weeks prior to planned start of repotrectinib or 5 half-lives, whichever is shorter.
•Any prior treatment with a TKI of ALK/ROS1/NTRK does NOT exclude subject from study.
3.All subjects must have measurable disease by RECIST v1.1 or RANO criteria at time of enrollment.
For Phase 2 subjects in Cohort 2 must have prospectively confirmed measurable disease by BICR prior to enrollment.
•Exception: Neuroblastoma subjects are permitted to have evaluable disease only.
4.Subjects with Primary CNS Tumors or metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 14 days prior to enrollment.
5.Subjects must have a Lansky (<16 years) or Karnofsky (≥16 years) score ≥50. Subjects who are unable to walk because of paralysis or tumor pain, but who are up in a wheelchair, will be considered ambulatory for the performance score.
6.Life expectancy ≥12 weeks.
7.Screening Local laboratory values:
ANC≥1.5 × 109/L, ≥0.75 × 109L, if known bone marrow involvement
PLT ≥100 × 109/L independent of platelets transfusion support for at least 7 days prior to dosing, ≥50 × 109/L, if known bone marrow involvement
Hemoglobin≥ 8.0 g/dL independent of red blood cell transfusion support for at least 7 days prior to dosing, unless bone marrow involvement identified at enrollment
Serum creatinine or creatinine clearance* Within normal limits per age or creatinine clearance or nuclear GFR>40 mL/min
Total serum bilirubin < 1.5 × ULN
AST/ALT<2.5 × ULN; <5 × ULN if liver metastases are present
ALP <2.5 × ULN; <5 × ULN if liver and/or bone metastasis are present.
Serum calcium, magnesium, and potassium: Normal or ≤CTCAE grade 1 with or without supplementation.
8.WOCBP must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. Female subjects will be considered to be of childbearing potential unless they have undergone permanent contraception or have premature menopause. For WOCBP and for men, agreement to use an effective contraceptive method from the time of screening until 5 weeks (WOCBP) or 6 months (men) after administration of the last dose of any study medication.
9.Ability to comply with study procedures.
10.The subject, parent or guardian must voluntarily sign and date an informed consent approved (in addition to pediatric assent, if required) by an IEC, prior to the initiation of any study specific procedures.
11.≤25 years at C1D1. |
1.Fase 2:UE no participa en cohorte 1.
Cohorte 2:Pacientes con tumores sólidos avanzados NTRK+(incluidos tumores primarios SNC)con tto previo inhibidores de TRK.Se requiere falta de respuesta,progresión o intolerancia al menos 1 o 2 inhibidores de TRK previo.Se permite cualquier número de líneas previas
Cohorte 3:En la UE(1)pacientes con fusiones NTRK sin enfermedad medible confirmada centralizadamente,pero son aptos para cohorte 2,y(2)sujetos con fusiones ROS1
Se requiere alteración genética documentada de ALK,ROS1 o NTRK1-3 identificada mediante pruebas locales en lab CLIA en USA o fuera
En pacientes incluidos mediante prueba de tejidos,debe enviarse tejido tumoral antes de inclusión al lab central.Cuando no haya tejido tumoral de archivo,se obtendrá uno de novo
En pacientes incluidos por biopsia líquida,se requerirá envío de muestras de sangre antes de inclusión al lab central
2.Los pacientes deben haberse recuperado de los efectos tóxicos agudos de las terapias previas antes de inclusión según CTCAE v4.03 grado≤1,excepción de alopecia.Pacientes no deben haber recibido:
-Quimioterapia:Última dosis administrada al menos 14 días o 5 semividas antes de repotrectinib
-Anticuerpos monoclonales(se excluyen anticuerpos terapéuticos inmunooncológicos [IO]):Última dosis al menos 21 días antes de repotrectinib
Inmunoterapia(ej;anticuerpos terapéuticos IO/vacuna tumoral):Paciente apto tras 28 días desde finalización antes de repotrectinib.Esteroides no considerados inmunoterapia.
Radioterapia:Sujetos no deben recibir radiación durante mínimo 2 sem antes de inclusión.Si es radiación extensa de médula ósea,al menos 42 días
Trasplante de CMHP:Pacientes aptos 12 sem después de infusión de CMHP autólogas después de terapia mieloablativa(desde D1 de repotrectinib).Los pacientes que hayan recibido infusión para respaldar terapia no mieloablativa (como131I metaiodobenzilguanidina)son aptos en cualquier momento si cumplen los demás criterios
Terapia con131I-MIBG:Mínimo 6 sem antes de repotrectinib
Factores de crecimiento:pacientes aptos 14 días después de última dosis de factor de crecimiento de acción prolongada o 7 días después de factor de crecimiento de acción corta
Cualquier fármaco en fase de investigación o terapia anticancerosa que no sea quimio y que no se especifique en otro lugar:no apto en 2 sem anteriores a repotrectinib o 5 semividas,lo que sea más corto
Cualquier tto previo con inhibidor de tirosina cinasa de ALK/ROS1/NTRK NO excluye al paciente del estudio
3.Los pacientes deben tener enfermedad medible según RECIST v1.1 o RANO en inclusión
para fase II:cohortes 1 y 2 deben tener enfermedad medible confirmada por BICR antes de inclusión Excepcion:Se permite que los pacientes con neuroblastoma tengan solo una enfermedad evaluable
4.pacientes con tumor primario del SNC o metástasis deben estar neurológicamente estables con dosis estable o decreciente de esteroides al menos 14 días antes de inclusión
5.Pacientes deben tener puntuación Lansky(<16 años) o Karnofsky(≥16 años)>50.Los pacientes que no puedan caminar por parálisis o por dolor del tumor,pero que se levanten en silla de ruedas,se considerarán ambulatorios para estado funcional
6.Esperanza de vida ≥12 semanas
7.Valores analíticos:
CAN≥1500/mm3(1,5×109/l);750/mm3(0,75×109/l),si la médula está afectada
Plaquetas≥100.000/mm3(100x109/l)independientemente del aporte de plaquetas por transfusión al menos 7 días antes de administración;≥50.000/mm3(50×109/l),si la médula está afectada
Hgb≥8,0 g/dl independientemente del aporte de glóbulos rojos por transfusión al menos 7 días antes de administración,a menos que haya afectación de médula en inclusión
Creatinina serica o depuración de creatinina:Dentro de LN o depuración de creatinina o TFG nuclear>40 ml/min
Bilirubina serica total:<1,5×LSN.Transaminasas hepaticas:<2,5xLSN;<5xLSN si hay metástasis hepáticas. Fosfatasa Alcalina:<2,5xLSN;<5xLSN si hay metástasis óseas y/o hepáticas.Ca,Mg y K séricos:Normal o grado ≤1 según CTCAE con o sin complementos
4.mujeres con capacidad de quedarse embarazadas deben dar negativo en prueba de embarazo en sangre durante el periodo de selección y no deben estar en lactancia o tener intención de quedarse embarazadas durante su participación.Las pacientes tienen capacidad de quedarse embarazadas,a menos que se hayan sometido a un método anticonceptivo permanente o tengan menopausia prematura.Estas mujeres capaces de quedarse embarazadas y los varones deben aceptar el uso de anticonceptivo efectivo desde la selección,durante el estudio y hasta 5 sem(para mujeres con capacidad de quedarse embarazas)o 6 meses(para varones)tras la última dosis de cualquier medicamento del estudio
5.Capacidad para cumplir con los procedimientos
6.El paciente,padres o tutor deben firmar y fechar voluntariamente una HIP aprobada(además del asentimiento del niño/a,si aplica)por un CEIm antes de iniciar cualquier procedimiento de selección o de estudio
7.≤25 años en D1 Ciclo 1 |
|
| E.4 | Principal exclusion criteria |
1. Concurrent participation in another therapeutic clinical trial.
2. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only.
3. Major surgery within 14 days (2 weeks) prior to Cycle 1 Day 1. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery.
4. Subjects who are pregnant or breast feeding.
5. Subjects with known active infections requiring ongoing treatment (bacterial, fungal, or viral, including HIV).
6. Subjects with gastrointestinal disease (eg, Crohn’s disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
7. Any of the following cardiac criteria:
• Mean resting corrected QT interval (electrocardiogram [ECG] interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 480 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec)
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval (Appendix 5)
8. Subjects with peripheral neuropathy with CTCAE grade ≥ 2.
9. Subjects with other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that, per the judgement of the Investigator or Sponsor, may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results, or make the subject inappropriate for entry into the study, or could compromise protocol objectives.
10. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers as listed in Appendix 4. |
1. Participación simultánea en otro ensayo clínico terapéutico.
2. Pacientes con neuroblastoma que solo tienen enfermedad de la médula ósea evaluable únicamente mediante aspirado de médula ósea.
3. Cirugía mayor en los 14 días (2 semanas) anteriores al D1 del ciclo 1. La colocación de un acceso venoso central (Broviac, Mediport, etc.) no cumple los criterios de cirugía mayor.
4. Pacientes que estén embarazadas o en periodo de lactancia.
5. Pacientes con infecciones activas conocidas que requieran tratamiento continuo (bacterianas, fúngicas o víricas, incluido el VIH).
6. Pacientes con una enfermedad gastrointestinal (p. ej., enfermedad de Crohn, colitis ulcerosa o síndrome de intestino corto) u otros síndromes de malabsorción que pudieran afectar a la absorción de medicamentos.
7. Cualquiera de los siguientes criterios cardiacos:
• Valor medio del intervalo QT en reposo corregido (intervalo en el electrocardiograma [ECG] medido desde el inicio del complejo QRS hasta el final de la onda T) del ritmo cardíaco (QTc) >480 ms obtenido de 3 ECG, empleando el valor del QTc obtenido con el electrocardiógrafo del centro en el periodo de selección.
• Toda anomalía clínicamente importante del ritmo, la conducción o la morfología del ECG en reposo (p. ej., bloqueo completo de la rama izquierda, bloqueo cardiaco de tercer grado, bloqueo cardiaco de segundo grado, intervalo PR >250 ms)
• Cualquier factor que pueda aumentar el riesgo de prolongación del QTc o de fenómenos arrítmicos, como insuficiencia cardíaca, hipopotasemia, síndrome de QT largo congénito, antecedentes familiares de síndrome de QT largo o cualquier medicación concomitante que se sabe que prolonga el intervalo QT ( Apéndice 5).
8. Pacientes con neuropatía periférica de grado ≥ 2 según los criterios CTCAE.
9. Pacientes con otras condiciones médicas o psiquiátricas agudas o crónicas graves o anomalías en analíticas que, a juicio del investigador o del promotor, puedan aumentar el riesgo asociado con la participación en el estudio o con la administración del fármaco del estudio, o que puedan interferir con la interpretación de los resultados del estudio, o que hagan que el paciente no sea apto para su inclusión en el estudio, o que puedan poner en riesgo el cumplimiento de los objetivos del protocolo.
10. Pacientes que estén en tratamiento o que prevean la necesidad de tratamiento con inhibidores o inductores potentes del CYP3A4, según la lista del Apéndice 4. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint for Phase 2:
• ORR as determined by BICR |
Criterio de valoración principal
Tasa de respuesta global (TRG) determinada por una revisión centralizada ciega e independiente (BICR, por sus siglas en inglés)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The ORR will be defined as the proportion of subjects with a confirmed complete response (CR) or partial response (PR). A confirmed response is a response that persists on a repeat-imaging performed at least 4 weeks after initial documentation of response. Subjects with a confirmed objective response (CR or PR) will be referred to as responders. Non-responders will include subjects without a confirmed objective response, SD, or PD.
The ORR will be reported as the proportion of responders along with the corresponding 2-sided 95% Clopper-Pearson exact CI. |
The ORR will be defined as the proportion of subjects with a confirmed complete response (CR) or partial response (PR). A confirmed response is a response that persists on a repeat-imaging performed at least 4 weeks after initial documentation of response. Subjects with a confirmed objective response (CR or PR) will be referred to as responders. Non-responders will include subjects without a confirmed objective response, SD, or PD.
The ORR will be reported as the proportion of responders along with the corresponding 2-sided 95% Clopper-Pearson exact CI.
|
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints for Phase 2:
• DOR, TTR, and CBR
• Intracranial tumor response
• Central nervous system progression-free survival (CNS-PFS) in subjects with measurable brain metastases
• PFS and OS
• Type, incidence, severity, timing, seriousness, and relatedness of AEs and laboratory abnormalities |
Variables secundarias para la Fase 2
Duración de respuesta (DR), Tiempo transcurrido hasta la respuesta (TTR), Tasa de beneficio clínico (TBC)
Tasa de respuesta objetiva intracraneal (TRO-IC)
Supervivencia libre de progresión del sistema nevioso central en pacientes con metastasis cerebral medible
Supervivencia libre de progresión y supervivencia global
Tipo, incidencia, intensidad, cronología, gravedad y relación con el fármaco del estudio de los AA y las anomalías en analíticas
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The DOR will be defined from the first date of objective response (either CR or PR) to first documentation of radiographic disease progression, as assessed by RECIST v1.1. The DOR will be censored at the last tumor assessment date for subjects without disease progression who have not died within 28 days of the last dose of study treatment.
The DOR will only be calculated for the subgroup of subjects with a confirmed objective tumor response. The DOR will be summarized in the populations of subjects with a confirmed CR or PR using the Kaplan-Meier method and will be displayed graphically where appropriate. The median event time (if appropriate) and 2-sided 95% CI for the median will be provided. |
| Duración de la respuesta (DR) se definirá desde la primera fecha de respuesta objetiva (CR o PR) hasta la primera documentación radiográfica de progresión de la enfermedad, según lo evaluado por RECIST v1.1. DR se censurará en la última fecha de evaluación del tumor para los sujetos sin progresión de enfermedad q no hayan fallecido en los 28 días posteriores a última dosis de tratamiento de estudio. DR solo se calculará para subgrupo de sujetos con respuesta tumoral objetiva confirmada. DR se resumirá en poblaciones de sujetos con CR o PR confirmado por el método de Kaplan-Meier y se mostrará gráficamente cuando sea apropiado. Se proporcionará la mediana del tiempo del evento (si corresponde) y un IC del 95% bilateral para la mediana. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Australia |
| Canada |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
| France |
| Spain |
| Italy |
| Denmark |
| United Kingdom |
|
| 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
|
| LVLS |
| Ultima visita ultimo paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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 |
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