| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute myeloid leukemia or myelodysplastic syndrome |
| Leucemia mieloide o síndrome mielodisplásico. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute myeloid leukemia or myelodysplastic syndrome |
| Leucemia mieloide o síndrome mielodisplásico. |
|
| 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 | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| 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 |
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 IB
Determinar 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 previamente
Fase II
Determinar 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 |
|
| E.2.2 | Secondary objectives of the trial |
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 interval
Randomized 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 |
|
| E.4 | Principal exclusion criteria |
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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 IB
Fase II:
Brazo único:
* respuesta completa
* Supervivencia total |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Due to the complexity of the study and the character limit in this section, please refer to the protocol for details of the timepoints of evaluation of the various primary endpoints. |
| Dada la complejidad del estudio y las características limitantes de esta sección, por favor, refiérase al protocolo para más detalles |
|
| E.5.2 | Secondary end point(s) |
Phase 1B Portion Secondary Endpoints
? Type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0), timing, seriousness, and relatedness of adverse events.
? Pharmacodynamic biomarkers.
? Pharmacokinetic parameters of PF-04449913, LDAC, decitabine and cytarabine/daunorubicin.
? CR/CRi
? Overall survival (OS).
? QTc interval.
Phase 2 Portion Secondary Endpoints
? OS for Phase 2 single arm component in fit patients (P2 Fit only).
? CR for Phase 2 randomized component in unfit patients (P2 Unfit only).
? For all AML patients: CIR, RFS, EFS, CID, and disease-specific efficacy endpoints, such as CRi, Morphologic Leukemia-Free State, Partial Remission (PR), Partial
Remission with incomplete blood count recovery (PRi), Minor Response (MR), Stable Disease (SD), Cytogenetic Complete Response (CRc), and Molecular
Complete Response (CRm).
? For all MDS patients: Hematologic Improvement (HI), marrow CR, Partial Remission (PR), Stable Disease (SD), Partial or Complete Cytogenetic Response, and CRi.
? Type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0), timing, seriousness, and relatedness of adverse events.
? Pharmacodynamic biomarkers.
? Pharmacokinetic parameters of PF-04449913.
? QTc interval. |
Fase IB:
*Clasificación de los acontecimientos adversos según la [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0
* Biomarcadores FD
* Parámetros FC de PF-04449913, LDAC, decitabine and cytarabine/daunorubicin
*
Fase 2:RC
*Supervivencia
Fase 2:
* ST
*RC
* RCi, RP, tipos de respuesta.
Clasificación de los acontecimientos adversos según la [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0
* Biomarcadores FD
* Parámetros FC de PF-04449913, LDAC, decitabine and cytarabine/daunorubicin
* |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Due to the complexity of the study and the character limit in this section, please refer to the protocol for details of the timepoints of evaluation of the various secondary endpoints. |
| Dada la complejidad del estudio y las características limitantes de esta sección, por favor, refiérase al protocolo para más detalles |
|
| 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 | Yes |
| 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 |
| Phase 1B: MTD & RP2D of PF-04449913 in combination with three other treatments |
|
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Germany |
| Italy |
| Poland |
| Spain |
| 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 Trial in all participating countries is defined as date upon which enrolment is completed according to protocol planned sample size and the assessments and requirements are completed according to protocol (including the follow up period). |
| El fin del estudio en todos los países participantes se define como la fecha en la que, habiéndose completado la inclusión de acuerdo con el tamaño de la muestra programado en el protocolo, se han finalizado las evaluaciones y requerimientos de acuerdo con el protocolo (esto incluye el período de seguimiento). |
|
| 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 | 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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