| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer (NSCLC) which represents 85% of all lung cancers. |
| Carcinoma pulmonar no microcítico (CPNM) que representa el 85% de todos los cánceres de pulmón. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung Cancer |
| Cáncer de pulmón |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 |
Part A
?To establish the safety and maximum tolerated dose (MTD) of AT13387 when administered in combination with crizotinib.
Part B
?To compare the PFS between the administration of single-agent crizotinib and the combination of crizotinib + AT13387 in subjects with NSCLC who will be treated with crizotinib or who were treated with
crizotinib and have not yet progress.
Part C
?To assess the efficacy (Objective Response Rate [ORR] = complete response [CR] + partial response [PR]) of single-agent AT13387 and to assess the efficacy of the addition of AT13387 to crizotinib in subjects
who progressed on treatment with crizotinib. |
Parte A
?Establecer la seguridad y la DMT de AT13387 cuando se administra en combinación con crizotinib.
Parte B
?Comparar la SLP entre la administración de crizotinib como agente único y la combinación de crizotinib + AT13387 en sujetos con CPNM que se van a tratar con crizotinib o que se trataron con crizotinib y aún no han progresado.
Parte C
?Evaluar la eficacia (tasa de respuesta objetiva [TRO] = respuesta completa [RC] + respuesta parcial [RP]) de AT13387 como agente único para evaluar la eficacia de la adición de AT13387 a crizotinib en sujetos que progresaron durante el tratamiento con crizotinib. |
|
| E.2.2 | Secondary objectives of the trial |
Part A
?To assess the pharmacodynamic depletion of relevant client proteins after treatment with AT13387;
?To assess the antitumor activity of the crizotinib + AT13387 combination (ORR [CR + PR]), circulating tumor cells (CTCs) response in patients with >5 CTCs/7.5 mL at baseline, progression-free survival (PFS), and overall survival (OS); and
?To assess the pharmacokinetic interaction between AT13387 and crizotinib.
Part B
?To assess the safety of AT13387 in combination with crizotinib in subjects with NSCLC;
?To compare the PFS and OS between crizotinib and crizotinib + AT13387; and
?To assess ORR (CR + PR) in crizotinib patients who crossover to crizotinib + AT13387.
Part C
?To assess the safety of AT13387 alone and in combination with crizotinib in subjects who progressed on crizotinib treatment and
?To assess and compare the PFS and OS of AT13387 administered alone or in combination with crizotinib in subjects who progressed on crizotinib treatment. |
Parte A
?evaluar la disminución farmacodinámica de proteínas cliente relevantes tras el tratamiento con AT13387
?evaluar la actividad antitumoral de la combinación de crizotinib + AT13387 (TRO [RC + RP]), la SLP y la supervivencia general (SG)
?evaluar la interacción farmacocinética entre AT13387 y crizotinib
Parte B
?evaluar la seguridad de AT13387 en combinación con crizotinib en sujetos con CPNM
?comparar la SG entre crizotinib y crizotinib + AT13387
?comparar la TRO entre crizotinib y crizotinib + AT13387 en sujetos con enfermedad medible al inicio
?evaluar la TRO (RC + RP) en los pacientes con crizotinib que se cambien a crizotinib + AT13387 y tengan enfermedad medible en el momento del cambio
Parte C
?evaluar la seguridad de AT13387 solo y en combinación con crizotinib en sujetos que progresaron durante el tratamiento con crizotinib
?evaluar y comparar la SLP y la SG de AT13387 administrado solo o en combinación con crizotinib en sujetos que progresaron durante el ... |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who meet all of the following criteria will be eligible to participate in the study:
1. Men or women ? 18 years of age;
2. Have a histologically or cytologically confirmed NSCLC that is ALK+ or has other mutations or rearrangements that are potentially sensitive to crizotinib and have been receiving or have received crizotinib, regardless of other prior anticancer therapies including other ALK inhibitors;
3. Presence of disease as described in Inclusion Criterion 4 for the different parts of the study;
4.a. In Part A, subjects must have received and been tolerant to at least 8 weeks of crizotinib 250 mg BID in the past regardless of when it was taken and the number of other intervening anticancer therapies, including other ALK inhibitors that may have been taken since the last dose of crizotinib. In part A, subjects with any response category may be enrolled as long as there is a chance of potential added benefit from continuing crizotinib in combination with AT13387 even if there is evidence of disease progression while on crizotinib monotherapy;
b. In Part B, subjects who are currently receiving and tolerating crizotinib and have not progressed by RECIST 1.1. or have not yet started but are eligible to receive crizotinib; and
c. In Part C, only subjects who are progressing or had previously progressed based on RECIST 1.1 at any time on crizotinib (including those who went on to receive other therapy including other ALK inhibitors before enrollment) will be enrolled;
5. Eastern Cooperative Oncology Group Performance Status ?1 for Part A and ?2 for Parts B and C;
6. Have adequate bone marrow function defined as absolute neutrophil count >1.5 K/?L and platelet count >75 K/?L;
7. Have adequate hepatic function, defined as bilirubin ?1.5 × upper limit of normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ?2.5 × ULN (ALT and AST ?5 × ULN, if liver metastases are present);
8. Have adequate renal function, defined as serum creatinine ?1.25 × ULN or estimated creatinine clearance >50 mL/min;
9. Have adequate cardiac function and normal cardiac repolarization defined as:
a. QTc ?480 msec and
b. Left ventricular ejection fraction ? 50% or within institutional limits of normal by echocardiogram or multigated acquisition scan;
10. Female subjects who are either:
a. Not pregnant (must have a negative pregnancy test at screening) or breastfeeding and not planning to become pregnant during the study;
b. Not of childbearing potential, defined as one who has been postmenopausal (no menses AND either age ?65 years or folliclestimulating hormone levels in the menopausal range) for at least 1 year, has been surgically sterilized by bilateral oophorectomy, or has had a hysterectomy;
11. Subjects and their female partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months following the last dose of the study drug. Effective contraception includes methods such as oral contraceptives, double-barrier method
(condom plus spermicide or diaphragm), or abstaining from sexual intercourse; and
12. Able and willing to provide written informed consent and to comply with the protocol and study procedures. |
1. hombres o mujeres ? 18 años de edad;
2. tener un CPNM confirmado histológica o citológicamente, que sea positivo para ALK o que tenga otras mutaciones o reorganizaciones que sean potencialmente sensibles a crizotinib, y haber estado recibiendo o haber recibido crizotinib, con independencia de otros tratamientos anticancerosos anteriores distintos de los inhibidores de la ALK;
3. presencia de enfermedad, según se describe en el criterio de inclusión 4 para las distintas partes del estudio;
4. a. en la Parte A, los sujetos deben haber recibido y sido tolerantes a al menos 8 semanas de crizotinib de 250 mg 2 v/d en el pasado, con independencia de cuándo se tomó y del número de tratamientos anticancerosos de intervención adicionales, incluidos otros inhibidores de la ALK que pueden haberse tomado desde la última dosis de crizotinib. En la Parte A, los sujetos con cualquier categoría de respuesta se pueden inscribir, siempre y cuando exista una posibilidad de beneficio potencial añadido si se continúa el tratamiento con crizotinib en combinación con AT13387, aún cuando exista evidencia de progresión mientras se recibe crizotinib en monoterapia;
b. en la Parte B, los sujetos que estén recibiendo y toleren actualmente crizotinib, y no hayan progresado según RECIST 1.1. o que no hayan empezado, pero que sean aptos para recibir crizotinib; y
c. en la Parte C, solo se inscribirá a los sujetos que progresen o hayan progresado previamente según RECIST 1.1 en cualquier momento mientras tomaban crizotinib (incluidos aquellos que siguieron recibiendo otro tratamiento, incluidos otros inhibidores de ALK antes de la inscripción);
5. Estado funcional del Grupo Oncológico Cooperativo del Este (ECOG) ? 1 para la Parte A y ? 2 para las Partes B y C;
6. tener una función adecuada de la médula ósea, definida por un recuento absoluto de neutrófilos > 1,5 K/?l y un recuento de plaquetas > 75 K/?l;
7. tener una función hepática adecuada, definida como un nivel de bilirrubina ? 1,5 veces el LSN y niveles de alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) ? 2,5 veces el LSN (ALT y AST ? 5 veces el LSN, en caso de presencia de metástasis hepática);
8. tener una función renal adecuada, definida como creatinina sérica ? 1,25 veces el LSN o aclaramiento de la creatinina estimado > 50 ml/min;
9. tener una función cardiaca adecuada y una repolarización cardiaca normal definida como:
a. QTc ? 480 ms; y
b. FEVI ? 50 % o dentro de los límites de la normalidad institucionales mediante ecocardiograma (ECO) o ventriculografía isotópica (MUGA);
10. sujetos mujeres que:
a. no estén embarazadas (deben tener una prueba de embarazo negativa en la selección) ni en período de lactancia y que no tengan pensado quedarse embarazas durante el estudio;
b. no sean fértiles, definido como una mujer que sea menopáusica (sin menstruaciones Y de ? 65 años o niveles de la hormona foliculoestimulante en el rango menopáusico) durante al menos 1 año, haya sido esterilizada quirúrgicamente mediante ooforectomía bilateral, o que se haya sometido a una histerectomía;
11. los sujetos y sus parejas mujeres en edad fértil deben aceptar utilizar métodos anticonceptivos eficaces durante el estudio y durante 3 meses después de la última dosis del fármaco del estudio. Los anticonceptivos eficaces incluyen métodos como los anticonceptivos orales, el método de doble barrera (preservativo más espermicida o diafragma) o abstención de mantener relaciones sexuales; y
12. ser capaz y estar dispuesto a dar su consentimiento informado por escrito para cumplir los procedimientos del protocolo y del estudio. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be excluded from the study:
1. Prior anti-cancer treatment with any heat shock protein 90 (HSP90) inhibitor;
2. Have received chemotherapy, radiation therapy, or other anticancer treatment other than crizotinib within 3 weeks prior to the first dose of study drug unless the washout period of those treatments has clearly exceeded 5 pharmacokinetic half-lives and any associated clinically significant toxicity has resolved to ?Grade 1;
3. Subjects with a prior malignancy other than adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, lowgrade cervical cancer, non-metastatic prostate cancer with normal PSA, or other cancer from which the subject has been disease-free for at least 3 years;
4. Known symptomatic brain or central nervous system metastases (Note: Patients with asymptomatic brain metastases or any brain metastases that have been stable for ? 4 weeks may be included);
5. Documented QTc prolongation >480 msec related to crizotinib on multiple measurements in electrocardiograms (ECGs) during prior
treatment with crizotinib;
6. ? Grade 2 bilirubin or transaminases on multiple measurements related to crizotinib while receiving crizotinib;
7. ? Grade 2 visual disturbances related to crizotinib while receiving crizotinib treatment;
8. Congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or clinically significant uncorrected electrolyte imbalance, particularly hypokalemia <3 mmol/L unless corrected;
9. Presence of a serious illness, active infection, medical condition, organ system dysfunction, or other factors which, in the Investigator's opinion, could compromise the subject's safety, negatively interact with AT13387, or compromise the integrity of the study outcomes;
10. Hypersensitivity to AT13387 or other components of the drug product;
11. For Part C, subjects who discontinued treatment with crizotinib due to a crizotinib-related toxicity;
12. Treatment with any investigational drug within 3 weeks prior to the first dose of study drug or at least until any residual clinically significant toxicity from the investigational agent has resolved to ? Grade 1 and at least 5 pharmacokinetic half-lives (if known) have elapsed;
13. Subjects who are a poor medical risk because of other systemic diseases or active uncontrolled infections; or
14. Known history of human immunodeficiency virus or seropositive test for hepatitis C virus or hepatitis B virus. |
1. tratamiento anticanceroso previo con cualquier inhibidor de HSP90;
2. haber recibido quimioterapia, tratamiento de radiación u otro tratamiento anticanceroso distinto de crizotinib dentro de las 3 semanas previas a la primera dosis del fármaco del estudio, a menos que el período de reposo farmacológico de estos tratamientos hayan excedido claramente 5 semividas farmacocinéticas y que cualquier toxicidad clínicamente significativa asociada se haya resuelto a ? grado 1;
3. los sujetos con una neoplasia maligna previa distinta de carcinoma de células escamosas o basales de la piel tratado de manera adecuada, cáncer de vejiga superficial, cáncer cervical de grado bajo, cáncer de próstata no metastásico con PSA normal u otro cáncer del que el sujeto haya estado libre de enfermedad durante al menos 3 años;
4. metástasis sintomática del sistema nervioso central o cerebral conocida (Nota: Los pacientes con metástasis cerebral asintomática o cualquier metástasis cerebral que haya permanecido estable durante ? 4 semanas se pueden incluir);
5. prolongación documentada de QTc > 480 ms relacionada con crizotinib en varias mediciones de ECG durante el tratamiento previo con crizotinib;
6. bilirrubina o transaminasas ? grado 2 en varias medidas relacionadas con crizotinib mientras se recibe crizotinib;
7. trastornos visuales ? grado 2 relacionados con crizotinib mientras se recibe el tratamiento con crizotinib;
8. síndrome de QT largo congénito, insuficiencia cardiaca congestiva, bradiarrítmias o desequilibrio electrolítico no corregido clínicamente significativo, en concreto hipopotasemia < 3 mmol/l a menos que se corrija;
9. presencia de una enfermedad grave, infección activa, afección médica, disfunción de sistema de órganos u otros factores que, en opinión del investigador, podrían comprometer la seguridad del sujeto, interactuar negativamente con AT13387 o comprometer la integridad de los resultados de estudio;
10. hipersensibilidad a AT13387 o a otros componentes del producto farmacológico;
11. en la Parte C, los sujetos que interrumpan el tratamiento con crizotinib debido a una toxicidad relacionada con crizotinib;
12. tratamiento con cualquier fármaco en investigación dentro de las 3 semanas antes de la primera dosis del fármaco del estudio o al menos hasta que cualquier toxicidad clínicamente significativa derivada del agente experimental se haya resuelto a ? grado 1 y hayan transcurrido al menos 5 semividas farmacocinéticas (si se conoce);
13. sujetos que tengan un mal riesgo médico debido a otras enfermedades sistémicas o a infecciones activas no controladas; o
14. antecedentes conocidos del virus de la inmunodeficiencia humana o prueba seropositiva para el virus de la hepatitis C o el virus de la hepatitis B. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A
?The incidence of DLTs when AT13387 is administered in combination with crizotinib.
Part B
?The comparison of PFS between crizotinib alone and the combination of crizotinib + AT13387.
Part C
?The ORR (CR + PR) for AT13387 alone and the ORR (CR + PR) for AT13387 + crizotinib at Stage 1 and Stage 2. |
Parte A
?La incidencia de TLD cuando AT13387 se administra en combinación con crizotinib.
Parte B
?La comparación de la SLP entre crizotinib solo y la combinación de crizotinib + AT13387.
Parte C
?La TRO (RC + RP) con AT13387 solo y la TRO (RC + RP) con AT13387 + crizotinib en la etapa 1 y en la etapa 2. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall Response Rate (ORR) and Overall Survival (OS) assessments are made every 8 weeks. |
| Las evaluaciones de la tasa general de respuesta (ORR) y de la supervivencia global (OS) se realizan cada 8 semanas. |
|
| E.5.2 | Secondary end point(s) |
Part A
?The HSP70 introduction as well as ALK and other client protein depletion after treatment with escalating doses of AT13387 in tumor biopsy;
?The incidence and severity of adverse events (AEs) at escalating doses of AT13387 administered in combination with crizotinib;
?The assessment of pharmacokinetic interaction between AT13387 and crizotinib; and
?The ORR (CR + PR), PFS, and OS in subjects receiving the combination of crizotinib + AT13387.
Part B
?The comparison of OS between crizotinib alone and the combination of crizotinib + AT13387,
?The comparison of AEs between crizotinib alone and the combination of crizotinib + AT13387,
?The comparison of ORR (CR + PR) between crizotinib and crizotinib + AT13387 for subjects with measurable disease at baseline; and
?The assessment of ORR (CR + PR) in crizotinib patients who crossover to crizotinib + AT13387 and have measurable disease at the time of crossover.
Part C
?PFS and OS for AT13387 alone and the combination of AT13387 + crizotinib,
?The incidence and severity of AEs for AT13387 alone and the combination of AT13387 + crizotinib, and
?The comparison of ORR and safety between AT13387 alone and the combination of AT13387 + crizotinib. |
Parte A
?la inducción de HSP70 así como la disminución de ALK y de otras proteínas cliente tras el tratamiento con dosis aumentadas de forma escalonada de AT13387 en la biopsia tumoral;
?la incidencia y la intensidad de los AA con incrementos de dosis de AT13387 administrado en combinación con crizotinib;
?la evaluación de la interacción farmacocinética entre AT13387 y crizotinib; y
?la TRO (RC + RP), la SLP y la SG en sujetos que reciban la combinación de crizotinib + AT13387.
Parte B
?la comparación de la SG entre crizotinib solo y la combinación de crizotinib + AT13387;
?la comparación de los AA entre crizotinib solo y la combinación de crizotinib + AT13387;
?la comparación de la TRO (RC + RP) entre crizotinib y crizotinib + AT13387 en sujetos con enfermedad medible al inicio; y
?la evaluación de la TRO (RC + RP) en pacientes con crizotinib que se cambien a crizotinib + AT13387 y que tengan enfermedad medible en el momento del cambio.
Parte C
?la SLP y la SG de AT13387 solo y de la combinación de AT13387 + crizotinib;
?la incidencia y la intensidad de los AA con AT13387 solo y con la combinación de AT13387 + crizotinib; y
?la comparación de la TRO y la seguridad entre AT13387 solo y la combinación de AT13387 + crizotinib. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall Response Rate (ORR) and Overall Survival (OS) assessments are made every 8 weeks.
Circulating tumor cells (CTC) are measured Cycle 1 Days 1 and 17, and then Day 1 of every subsequent cycle. |
Las evaluaciones de la tasa general de respuesta (ORR) y de la supervivencia global (OS) se realizan cada 8 semanas.
Las células tumorales circulantes (CTC) se miden en el ciclo 1 Días 1 y 17 y a continuación en cada ciclo posterior. |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| A 3 part Phase 1-2 study to assess safety and efficacy |
| Un estudio Fase 1-2 de 3 partes para evaluar la seguridad y eficacia |
|
| 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 | 5 |
| 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 | 13 |
| 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 |
|
| 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
|
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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