Hemotrial Un proyecto de SEHH

Ensayo clínico

A Phase 1B/2 Study To Evaluate The Safety And Efficacy of PF-04449913, An Oral Hedgehog Inhibitor, In Combination With Intensive Chemotherapy, Low Dose ARA-C Or Decitabine In Patients With Acute Myeloid Leukemia Or High-Risk Myelodysplastic Syndrome ESTUDIO EN FASE IB/II PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE PF-04449913, INHIBIDOR ORAL DE LA VÍA HEDGEHOG, EN COMBINACIÓN CON QUIMIOTERAPIA INTENSIVA, DOSIS BAJAS DE ARA-C O DECITABINA, ADMINISTRADO A PACIENTES CON LEUCEMIA MIELOIDE AGUDA O SÍNDROME MIELODISPLÁSICO DE ALTO RIESGO.

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Resumen

2017-03-15 04:26:51
2012-000684-24
B1371003
A Phase 1B/2 Study To Evaluate The Safety And Efficacy of PF-04449913, An Oral Hedgehog Inhibitor, In Combination With Intensive Chemotherapy, Low Dose ARA-C Or Decitabine In Patients With Acute Myeloid Leukemia Or High-Risk Myelodysplastic Syndrome ESTUDIO EN FASE IB/II PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE PF-04449913, INHIBIDOR ORAL DE LA VÍA HEDGEHOG, EN COMBINACIÓN CON QUIMIOTERAPIA INTENSIVA, DOSIS BAJAS DE ARA-C O DECITABINA, ADMINISTRADO A PACIENTES CON LEUCEMIA MIELOIDE AGUDA O SÍNDROME MIELODISPLÁSICO DE ALTO RIESGO.
B1371003

PROMOTORES DEL ENSAYO
Nombre del promotor Organización Persona de contacto País
Pfizer Inc. 235 East 42nd Street, New York, NY 10017 Pfizer Inc Clinical Trials.gov Call Center United States

Fármacos

  INFORMACIÓN DE FÁRMACOS USADOS:
  FÁRMACO 1:
Test
N/A PF-04449913
Tablet
Oral use

Detalles del Fármaco (Principio Activo):

PF-04449913 1-((2R,4R)-2-(1

Concentración del fármaco:

mg milligram(s) equal

10

Contenido del fármaco


Si
No

No
No

No
No

No
No

No
No

No
No

No
  FÁRMACO 2:
Test
N/A PF-04449913
Tablet
Oral use

Detalles del Fármaco (Principio Activo):

PF-04449913 1-((2R,4R)-2-(1

Concentración del fármaco:

mg milligram(s) equal

25

Contenido del fármaco


Si
No

No
No

No
No

No
No

No
No

No
No

No
  FÁRMACO 3:
Test
PF-04449913
Tablet
Oral use

Detalles del Fármaco (Principio Activo):

PF-04449913 1-((2R,4R)-2-(1

Concentración del fármaco:

mg milligram(s) equal

100

Contenido del fármaco


Si
No

No
No

No
No

No
No

No
No

No
No

No
  FÁRMACO 4:
Test
Solution for injection
Intravenous useSubcutaneous use

Detalles del Fármaco (Principio Activo):

. .

Concentración del fármaco:

mg/ml milligram equal

100

Contenido del fármaco


Si
No

No
No

No
No

No
No

No
No

No
No

No
  FÁRMACO 5:
Test
Lyophilisate for solution for injection
Intravenous use

Detalles del Fármaco (Principio Activo):

. DAUNORUBICIN HY

Concentración del fármaco:

mg milligram(s) equal

20

Contenido del fármaco


Si
No

No
No

No
No

No
No

No
No

No
No

No
  INFORMACIÓN DE PLACEBOS USADOS:

No hay placebos asignados al ensayo

Información General



Síndrome Mielodisplásico, Leucemia Aguda

Acute myeloid leukemia or myelodysplastic syndrome Leucemia mieloide o síndrome mielodisplásico.


Phase 1B Portion:? To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of PF-04449913 in combination with low dose ARA-C (LDAC; Arm A), decitabine (Arm B) or cytarabine/daunorubicin (Arm C) when administered to adults with previously untreated AML or high-risk MDS.Phase 2 Portion:Single Arm Component in Fit Patients:? To determine the rate of complete remission (CR) of PF-04449913 when administered in combination with cytarabine/daunorubicin to fit patients with previously untreated AML or high-risk MDS.Randomized Component in Unfit Patients:? To compare the overall survival (OS) for PF-04449913 + LDAC versus LDAC alone in unfit patients with previously untreated AML or high risk MDS. Fase IBDeterminar la dosis máxima tolerada (DMT) y la dosis recomendada para la fase II (DRF2) de PF-04449913 en combinación con dosis bajas de Ara-C (DBAC; grupo A), con decitabina (grupo B) o con citarabina/daunorrubicina (grupo C), al ser administrado a adultos con LMA o SMD de alto riesgo no tratados previamente.Componente aleatorizado de la fase II en pacientes en condiciones no adecuadas (F2 CNA)* Comparar la supervivencia global (SG) de PF-04449913 + DBAC frente a DBAC sola en pacientes en condiciones no adecuadas con LMA o SMD de alto riesgo no tratados previamenteFase IIDeterminar el porcentaje de remisión completa (RC) de PF-04449913 al administrarse en combinación con citarabina/daunorrubicina en pacientes en condiciones adecuadas con LMA o SMD de alto riesgo no tratados previamente

For the secondary objectives of the Phase 1B Portion, please refer to the protocol.Phase 2 Portion:Single Arm Component in Fit Patients:? Efficacy of PF-04449913 in combination with cytarabine/daunorubicin? Safety & tolerability of PF-04449913 in combination with cytarabine/daunorubicin? PD of PF-04449913 in combination with cytarabine/daunorubicin? PK of PF-04449913? Characterize the effects of PF-04449913 on QTc intervalRandomized Component in Unfit Patients? Efficacy of PF 04449913 in combination with LDAC versus LDAC alone? Safety and tolerability of PF 04449913 when administered in combination with LDAC versus LDAC alone? PD of PF 04449913 when administered in combination with LDAC versus LDAC alone? PK of PF 04449913 Para objetivos secundarios de la fase 1B, por favor referisre al protocolo. Fase II:Evaluar las medidas de eficacia clínica de PF-04449913 al administrarse en combinación con citarabina/daunorrubicina en pacientes en condiciones adecuadas ? Determinar la seguridad y tolerabilidad de PF-04449913 al administrarse en combinación con citarabina/daunorrubicina en pacientes en condiciones adecuadas.? FDde PF-04449913 al administrarse en combinación con citarabina/daunorrubicina.?FC de PF-04449913.? efectos de PF-04449913 sobre el intervalo QTc.Componente aleatorizado de la fase II en pacientes en condiciones no adecuadas (F2 CNA)medidas de eficacia clínica de PF-04449913 en combinación con DBAC frente a DBAC? seguridad y tolerabilidad de PF-04449913 en combinación con DBAC frente a DBAC sola.? FD PF-04449913 cuando se administra en combinación con DBAC frente a DBAC sola.? FC de PF-04449913.? efectos de PF-04449913 sobre el intervalo QTc.

No


Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:1. Patients with AML or RAEB-2 High-Risk MDS who are newly diagnosed according to the WHO 2008 Classification and previously untreated. Eligible patients with AML arising from an antecedent hematologic disease (AHD) or MDS may have had one prior regimen with commercially-available agent(s) (eg, azacytadine or decitabine) for the treatment of their prior hematologic disease. The patients may not have had a prior therapy for their AML.Patients enrolling in the P2 Unfit Arms must have a known cytogenetic profile at study entry.2. AML patients include de-novo AML, AML evolving from MDS or other AHD and AML after previous cytotoxic therapy or radiation (secondary AML).? For a diagnosis of AML, a bone marrow blast count of 20% or more is required. ? For AML defined by cytogenetic aberrations t(8;21), inv(16) or t(16;16) and some cases of erythroleukemia the proportion of bone marrow blasts may be <20%.? In AML FAB M6a (erythroid leukemia) ?30% of non erythroid cells in the bone marrow must be leukemic blasts.? In AML with monocytic or myelomonocytic differentiation, monoblasts and promonocytes, but not abnormal monocytes, are counted as blast equivalents.3. For a diagnosis of high-risk Myelodysplastic Syndrome RAEB-2 the patient must have 10-19% bone marrow blasts (See Appendix 3 of the protocol).4. Age:? ?18 years old for patients enrolled in Phase 1B and P2 Fit Arm? ?55 years old for patients enrolled in the P2 Unfit Arms.5. ECOG Performance Status 0, 1, or 2.6. Patients with AML or High-Risk MDS who have one or more of the criteria below are considered unfit for intensive chemotherapy (Kantarjian et al, 2006) and are eligible for Phase 1B Arms A and B or P2 Unfit Arms:? Age ?75 years. ? ECOG of 2.? Serum creatinine >1.3 mg/dL.? Severe cardiac disease (eg, LVEF <45% by multigated acquisition [MUGA] or echocardiography [ECHO] at screening).7. Patients with AML or high risk MDS and have none of the following criteria are considered fit for more intensive chemotherapy and are only eligible for Phase 1B Arm C or P2 Fit Arm:? ECOG of 2.? Serum creatinine >1.3 mg/dL.? Severe cardiac disease (eg, LVEF <45% by MUGA or ECHO at screening).8. Adequate Organ Function as defined by the following:? Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ?3 x upper limit of normal (ULN), or AST and ALT ?5 x ULN if liver function abnormalities are due to underlying malignancy.? Total serum bilirubin ?2 x ULN (except patients with documented Gilbert?s syndrome).? Serum creatinine ?1.5 x ULN or estimated creatinine clearance ?60 mL/min as calculated using the method standard for the institution. 9. All anti-cancer treatments (unless specified) should be discontinued ?2 weeks from study entry (defined in Section 6 of the protocol), for example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines. ? For control of rapidly progressing leukemia, hydroxyurea or leukapheresis may be used before and for up to 1 week after first dose of PF-04449913 for all three arms of the study. ? Patients with controlled CNS leukemia (documented by two consecutive assessments of zero blast count in cerebrospinal fluid), and who are still receiving intrathecal (IT) therapy at study entry are considered eligible, and will continue to receive IT therapy.10. Resolved acute effects of any prior therapy to baseline severity or Grade ?1 CTCAE e

Patients presenting with any of the following will not be included in the study:1. AML M3 Acute Promyelocytic Leukemia (APL) or patients with a t(9:22) cytogenetic translocation for any component of the study. 2. Hyperleukocytosis (leukocytes ?30 x 109/L) at study entry. These patients may be treated with hydroxyurea or receive leukopheresis treatment according to routine practice, and enrolled in the study when the leukocyte count falls below 30 x 109/L.3. Patients in whom, at the time of study entry, a stem cell transplant is planned within the next 6 months.4. Patients known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.5. Patients with active malignancy with the exception of basal cell carcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior or concurrent malignancies will be considered on a case-by-case basis.6. For fit patients (Phase IB Arm C or P2 Fit Arm):? LVEF <45% by ECHO or MUGA scan. ? Cumulative anthracyline dose equivalent of ?250 mg/m^2 of daunorubicin or ?125 mg/m^2 of idarubicin.7. Any one of the following currently or in the previous 6 months: myocardial infarction, congenital long QT syndrome, torsades de pointes or clinically significant ventricular arrhythmias. 8. QTc interval >470 msec using the Fridericia (QTcF).9. Patients with an active, life threatening or clinically significant uncontrolled systemic infection.10. Patients with known active uncontrolled central nervous system (CNS) leukemia.11. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness or active Hepatitis B or C infection.12. Known malabsorption syndrome or other condition that may impair absorption of study medication (eg, gastrectomy or lap band).13. Major surgery or radiation within 4 weeks of starting study treatment.14. Prior treatment with? a Hedgehog inhibitor at any time? an investigational agent for the treatment of an antecedent hematologic disease (AHD).15. Prior treatment with decitabine or azacitidine (Phase 1B Arm B only), or cytarabine (Phase 1B Arm A and P2 Unfit only).16. The presence of any one of the following hypersensitivities: ? For patients receiving cytarabine on study (Phase 1B Arm A, P2 Fit and P2 Unfit Arms only): Hypersensitivity to cytarabine (not including drug fever or exanthema). ? For patients receiving decitabine on study (Phase 1B Arm B): hypersensitivity to decitabine. ? For patients receiving daunorubicin on study (Phase 1B Arm C and P2 Fit Arm): hypersensitivity to daunorubicin. 17. Concurrent treatment with any investigational or approved oncology agents (unless specified in the protocol).18. Concurrent administration of herbal preparations.19. Current use or anticipated need for food or drugs that are known strong/moderate CYP3A4 inhibitors, including their administration within 7 days prior to study entry. Please refer to Section 5.5 of the protocol for list of prohibited inhibitors.20. Current use or anticipated need for drugs that are known strong CYP3A4 inducers, including their administration within 7 days prior to study entry. Please refer to Section 5.5 of the protocol for list of prohibited inducers.21. Current use or anticipated need for drugs that are CYP3A4 substrates with a narrow therapeutic index or are P-glycoprotein inhibitors/inducers, including their administration within 7 days prior to study entry. Please refer to Section 5.5 of the protocol for list of narrow therapeutic index CYP3A4 substrates and P-gp inhibitors/inducers. 22. Current drug or alcohol abuse.23. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.24. Patients who are investigational site staff members or relatives of those site staff members or patients who are Pfizer employees directly involved in the conduct of the trial.25. Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 90 days after last dose of investigational product; males and females of childbearing potential not using two (2) methods of highly effective contraception or not agreeing to continue two (2) methods of highly effective contraception for at least 90 days after last dose of investigational product.26. Recent or active suicidal ideation or behavior. Leucemia promielocítica aguda M3 (LPA) o pacientes con la traslocación citogenética t(9:22) en cualquier componente del estudio.2. Hiperleucocitosis (leucocitos ? 30 x 109/l) al inicio del estudio. Estos pacientes podrán ser tratados con hidroxiurea o leucaféresis, de acuerdo con la terapia habitual del centro, pudiendo ser incluidos en el estudio cuando la cifra de leucocitos descienda por debajo de 30 x 109/l.3. Pacientes en los que, en el momento de la inclusión en el estudio, tengan programado un trasplante de hemocitoblastos en los 6 meses siguientes.4. Pacientes con refractariedad conocida a las transfusiones de plaquetas o concentrados de hematíes según los protocolos del centro, así como los que rechacen las transfusiones de hemoderivados.5. Pacientes con neoplasias activas, a excepción del carcinoma de células basales, el cáncer de piel no melanoma y el carcinoma localizado de cuello uterino. Otras neoplasias concomitantes o previas se considerarán caso por caso.6. Para los pacientes en condiciones adecuadas (Grupo C de la fase IB o grupo F2 CA):? FEVI < 45 % determinada mediante ecocardiograma o ventriculografía isotópica (MUGA).? Dosis de antraciclina acumulada equivalente a ? 250 mg/m2 de daunorrubicina o > 125 mg/m2 de idarrubicina.7. Cualquiera de los siguientes trastornos presentes en la actualidad o en los 6 meses anteriores: infarto de miocardio, síndrome del QT largo congénito, taquicardia ventricular en entorchado o arritmias ventriculares clínicamente significativas.8. Intervalo QTc > 470 ms, corregido mediante el método de Fridericia (QTcF).9. Pacientes con una infección activa, no controlada, potencialmente mortal o clínicamente significativa.10. Pacientes con afectación leucémica conocida del sistema nervioso central (SNC), activa y no controlada.11. Infección conocida por el virus de la inmunodeficiencia humana (VIH), enfermedad relacionada con el síndrome de inmunodeficiencia adquirida (SIDA) o hepatitis B o C activa.12. Síndrome de malabsorción diagnosticado u otro trastorno que pueda afectar a la absorción de la medicación del estudio (p. ej., gastrectomía o banda gástrica).13. Cirugía mayor o irradiación en las 4 semanas previas al inicio del tratamiento del estudio.

Phase 1B Portion Primary Endpoint:? First cycle dose limiting toxicities (DLTs). Phase 2 Portion Primary Endpoints:Single Arm Component in Fit Patients (P2 Fit)? Complete response (CR).Randomized component in Unfit Patients (P2 Unfit)? Overall survivial (OS). Fase IB:La toxicidad limitante de la dosis (TLD) es la variable primaria de la fase IBFase II:Brazo único:* respuesta completa* Supervivencia total

Fase IFase I-IIFase II
  DISEÑO DEL ENSAYO:

No
No

Si
Information no disponible en EudraCT

Information no disponible en EudraCT
Information no disponible en EudraCT

Information no disponible en EudraCT
Information no disponible en EudraCT
  COMPARADOR DEL ENSAYO CONTROLADO:

Information no disponible en EudraCT
Information no disponible en EudraCT

Information no disponible en EudraCT
No

Si

Centros participantes:


Si
No
  TIEMPO ESTIMADO DURACIÓN DEL ENSAYO:

3
0
  TIEMPO ESTIMADO DURACIÓN DEL ENSAYO EN ESPAÑA:


  POBLACIÓN DE PACIENTES EN EL ESTUDIO:
  Población de pacientes: 1

Rango de edad:


0
1

1

Sexo:


1
1

Número planeado de pacientes a incluir:


8

Para estudios internacionales:


150
175

Investigadores

  INVESTIGADORES QUE PARTICIPAN EN EL ESTUDIO

Estado actual


Por Determinar



En Marcha