| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
Phase Ib: To determine the MTD and/or RP2D of HDM201 in combination with LEE011 in patients with liposarcoma.
Phase2: To assess the preliminary anti-tumor activity of HDM201 in combination with LEE011 in patients with liposarcoma. |
Fase Ib: Determinar la DMT y/o la DRF2 de HDM201 en combinación con LEE011 en pacientes con liposarcoma.
Fase II: Evaluar la actividad antitumoral de HDM201 en combinación con LEE011 en pacientes con liposarcoma. |
|
| E.2.2 | Secondary objectives of the trial |
Phase1b/2:
1. To characterize the safety and tolerability of HDM201 in combination with LEE011
2. To characterize the pharmacokinetic (PK) properties of HDM201 in combination with LEE011 and potential metabolite/s when feasible
3. To assess the pharmacodynamic (PD) effect of HDM201 in combination with LEE011 and a potential relationship with clinical outcome
Phase Ib:
To assess preliminary anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma
Phase II
To further assess the anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma |
Fase Ib/II
Caracterizar la seguridad y la tolerabilidad de HDM201 en combinación con LEE011.
Caracterizar las propiedades farmacocinéticas (PK) de HDM201 en combinación con LEE011 y los posibles metabolitos, si procede.
Evaluar el efecto farmacodinámico (PD) de HDM201 en combinación con LEE011 y una posible relación con los resultados clínicos.
Fase Ib
Evaluar la actividad antitumoral preliminar de HDM201 en combinación con LEE011 en liposarcoma.
Fase II
Evaluar más a fondo la actividad antitumoral de HDM201 en combinación con LEE011 en liposarcoma. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
? Male or Female age 18 years or older.
? Patients with histologically documented, locally advanced or metastatic WD/DD liposarcoma that has progressed on/or despite one prior systemic therapy.
? Patients with radiographic progression, defined by RECIST v.1.1, occurring while on/or within 6 months after last systemic treatment, prior to enrollment.
? Patients must have disease that can be evaluated by RECIST v1.1; measurable disease is required for patients enrolled in the Phase II.
? ECOG performance status of 0-1.
? Patients suitable and willing to undergo baseline biopsy.
Other protocol-defined inclusion criteria may apply |
? Pacientes de ambos sexos ? 18 años de edad.
? Pacientes con liposarcoma BD/DD localmente avanzado o metastásico histológicamente documentado que haya progresado con/o a pesar de un tratamiento sistémico previo.
? Pacientes con progresión radiográfica, definida según los criterios RECIST v.1.1, que ocurra durante el último tratamiento sistémico antes de la inclusión o durante los 6 meses posteriores al mismo.
? Los pacientes deben presentar enfermedad que pueda evaluarse según los criterios RECIST v1.1. Los pacientes incluidos en la fase II deben presentar enfermedad medible.
? Estado funcional ECOG de 0-1.
? Pacientes aptos para la realización de una biopsia basal y que deseen someterse a la misma. |
|
| E.4 | Principal exclusion criteria |
? Prior treatment with compounds with the same mode of action.
? Patients with TP53 mutated tumors, if the molecular status is known.
? Symptomatic central nervous system metastases.
? Impaired cardiac function.
? Inadequate organ function.
? Concomitant treatment with: Restriction in the use of moderate to strong inhibitors or inducers of CYP3A4/5, substrates of CYP3A4/5 with a narrow therapeutic index or medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
? Concomitant treatment with colony-stimulating growth factors targeting the myeloid lineage (e.g. G-CSF, GM-CSF, M-CSF).
Other protocol-defined exclusion criteria may apply |
? Tratamiento previo con compuestos con el mismo modo de acción.
? Pacientes con tumores con mutación TP53, en caso de que el estado molecular sea conocido.
? Metástasis sintomáticas en el sistema nervioso central.
? Deterioro de la función cardíaca.
? Función orgánica inadecuada.
? Tratamiento concomitante con: Restricción en el uso de inhibidores o inductores de moderados a potentes de CYP3A4/5, sustratos de CYP3A4/5 con un índice terapéutico estrecho o medicación con un riesgo conocido de prolongar el intervalo QT o de inducir torsades de pointes.
? Tratamiento concomitante con factores de crecimiento estimuladores de colonias dirigidos al linaje mieloide (p. ej., G-CSF, GM-CSF, M-CSF). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase1b:
1. Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment
2. Exposure to HDM201 and LEE011 as measured by AUC0-24h at C1D14
Phase 2:
PFS as per RECIST 1.1, assessed by investigator |
Fase 1b:
Incidencia de toxicidades limitantes de dosis (TLD) durante el primer ciclo de tratamiento.
Exposición a HDM201 y LEE011 medida mediante el AUC0-24h el D14C1
Fase 2:
SLP evaluada por el investigador según los criterios RECIST 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase1b:
1. First cycle of treatment (28 days for Regimen 1 and 3 / 35 days for Regimen 2)
2. For all regimens: on D1, 2, 8, 14, 15 for Cycle1
Phase 2:
PFS at 12 and 24 weeks |
Fase 1b:
1. Primer ciclo de tratamiento (28 días para régimen 1 y 3 / 35 días para régimen 2)
2.Para todos los regímenes: en D1, 2, 8, 14, 15 para CYCLE1
Fase 2:
SLP en 12 y 24 semanas |
|
| E.5.2 | Secondary end point(s) |
Phase 1b/2:
1. Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs, ECG
Tolerability: Dose interruptions, reductions and dose intensity.
2. Time vs. plasma concentration profiles, PK parameters of HDM201 and LEE011 and potential metabolite/s when feasible
3. Anti-tumor activity endpoint (BOR, PFS) and changes from baseline of PD markers:
- In tumor tissue (e.g. p21, PUMA, MDM2)
- In blood (e.g. GDF-15)
Phase1b:
BOR, ORR and PFS as per RECIST v1.1, assessed by investigator
Phase 2:
- BOR, ORR and DOR as per RECIST v 1.1 assessed by investigator
- OS |
Fase 1b/2:
Seguridad: Incidencia y gravedad de AA y AAG, incluidos los cambios en los valores de laboratorio, las constantes vitales y el ECG
Tolerabilidad: Interrupciones, reducciones e intensidad de la dosis.
Perfiles de tiempo frente a concentración plasmática, parámetros PK de HDM201 y LEE011 y posibles metabolitos, si procede.
Variable de la actividad antitumoral (MRG, SLP) y cambios respecto a la basal de los marcadores PD:
-En tejido tumoral (p. ej., p21, PUMA, MDM2).
-En sangre (p. ej., GDF-15).
Fase 1b:
MRG, TRG y SLP evaluadas por el investigador según los criterios RECIST 1.1.
Fase 2:
MRG, TRG y DR evaluadas por el investigador según los criterios RECIST 1.1.
SG |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1b/2:
1. Every cycle
2. For all regimens: on D1, 2, 8, 14, 15 for Cycle1 - on D1, 8, 14 for Cycle 2 and on D14 for Cycle 3 and 4
3. Baseline, up to 14 days
Phase1b:
BOR, ORR and PFS at 6 months
Phase 2:
- BOR, ORR and DOR at 6 months
- OS at 12 months |
Fase 1b/2:
1. Cada ciclo
2. Para todos los regímenes: en D1, 2, 8, 14, 15 para el ciclo 1 - en D1, 8, 14 para ciclo 2 y en D14 para ciclos 3 y 4
3. Baselina, hasta 14 días
Fase 1b:
MRG, TRG y SLP a los 6 meses
Fase 2:
- MRG, TRG y DR a los 6 meses
- SG a los 12 meses |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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) | 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 |
|
| 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
| 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 | 5 |
| 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 |
| Canada |
| France |
| Germany |
| Singapore |
| Spain |
| Taiwan |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| End of study will be upon completion of the safety follow-up disease for all patients, progression follow-up and end of survival follow-up for phase II patients, whichever comes later, or if the study is terminated early. |
| El fin del estudio tendrá lugar cuando finalice el seguimiento de la seguridad de todos los pacientes, el seguimiento de la progresión y el seguimiento de la supervivencia de los pacientes de la fase II, aquello que ocurra más tarde, o si el estudio finaliza prematuramente |
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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 | |
| E.8.9.1 | In the Member State concerned months | 28 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
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