E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelodysplastic syndromes (MDS) Chronic myelomonocytic leukemia (CMML) |
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E.1.1.1 | Medical condition in easily understood language |
Myelodysplastic syndromes (MDS) Chronic myelomonocytic leukemia (CMML) |
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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 | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028536 |
E.1.2 | Term | Myelodysplastic syndromes |
E.1.2 | System Organ Class | 100000004851 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009018 |
E.1.2 | Term | Chronic myelomonocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
To assess and compare overall survival (OS) between guadecitabine and treatment choice (TC) in adults with MDS or CMML previously treated with a hypomethylating agent (azacitidine or decitabine, or both).
TC options are low dose cytarabine (LDAC), standard intensive chemotherapy (IC) of a 7+3 regimen (cytarabine and an anthracycline given as per institutional standard practice), or best supportive care only (given according to standard and institutional practice).
Best supportive care will be provided to all subjects as per standard and institutional practice. |
Objetivo principal • Evaluar y comparar la supervivencia global (SG) entre guadecitabina y el tratamiento de elección (TE) en adultos con SMD o LMMC tratados previamente con agentes hipometilantes (azacitidina, decitabina o ambos). |
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E.2.2 | Secondary objectives of the trial |
To assess and compare effects of guadecitabine and TC in adults with MDS or CMML previously treated with a hypomethylating agent (azacitidine or decitabine, or both) with respect to the following variables:
- Transfusion independence. - Marrow complete response (mCR) with transfusion independence. - Survival rate at 1 year after randomization. - Leukemia-free survival. - Number of days alive and out of the hospital (NDAOH). - Disease response based on IWG 2006 MDS criteria including complete response (CR), partial response (PR), mCR, and hematological improvement (HI; erythroid, platelet, or neutrophil response); and duration of response. - Number of red blood cell (RBC) and platelet transfusions. - Health-related quality of life (QOL). - Safety.
Exploratory: Assess influence of demographic characteristics, disease characteristics, and molecular biomarkers on treatment outcomes; evaluate pharmacokinetic exposure-response relationships with efficacy and safety parameters. |
Objetivos secundarios Evaluar y comparar los efectos de guadecitabina y el TE en adultos con SMD o LMMC tratados previamente con agentes hipometilantes (azacitidina, decitabina o ambos), con respecto a las siguientes variables: •Independencia de transfusiones. •Respuesta completa medular (RCm) con independencia de transfusiones. •Tasa de supervivencia a 1 año después de la aleatorización. •Supervivencia libre de leucemia. •Número de días en que el paciente está vivo y sin hospitalizar (NDVSH). •Respuesta de la enfermedad conforme a los criterios de 2006 del grupo de trabajo internacional (IWG, International Working Group) para la evaluación de la respuesta en los SMD, que incluye respuesta completa (RC), respuesta parcial (RP), RCm y mejora hematológica (MH; respuesta de eritrocitos, plaquetas o neutrófilos); y duración de la respuesta. •Número de eritrocitos (NE) y transfusiones de plaquetas. •Calidad de vida (CDV) relacionada con la salud. •Seguridad. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult subjects ≥18 years of age who are able to understand and comply with study procedures, and provide written informed consent before any study-specific procedure. 2. Cytologically or histologically confirmed diagnosis of MDS or CMML according to the 2008 World Health Organization (WHO) classification. 3. Performance status (Eastern Cooperative Oncology Group [ECOG]) of 0-2. 4. Subjects with previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows: a. Subject received HMA for at least 6 cycles and was still transfusion dependent (as defined in 5b below). b. Subject had disease progression prior to Cycle 6 defined as ≥50% increase in bone marrow blasts from pretreatment levels to >5%, or ≥2 g/dL reduction of Hgb from pretreatment levels with transfusion dependence after at least 2 cycles of HMA. Other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed. 5. Subjects must have either: a. Bone marrow blasts >5% at randomization, OR b. Transfusion dependence, defined as having had transfusion (in the setting of active disease) of 2 or more units of RBC or platelets within 8 weeks prior to randomization. 6. Creatinine clearance or glomerular filtration rate ≥30 mL/min estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration). 7. Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential and men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to become pregnant or father a child while receiving treatment with guadecitabine, LDAC, or IC and for at least 3 months after completing treatment. |
Los sujetos deben cumplir todos los criterios de inclusión siguientes. 1. Adultos de edad ≥18 años, capaces de comprender y cumplir los procedimientos del estudio y proporcionar el consentimiento informado por escrito antes de que estos se lleven a cabo. 2. Diagnóstico de SMD o LMMC confirmado mediante citología o histología, de acuerdo con la clasificación de 2008 de la Organización Mundial de la Salud (OMS). 3. Estado funcional según el ECOG (Eastern Cooperative Oncology Group) de 0 a 2. 4. Sujetos con SMD o LMMC tratados anteriormente, esto es, que hayan recibido previamente al menos un agente hipometilante (AHM; azacitidina, decitabina o ambos) para SMD o LMMC de riesgo medio o alto, y con progresión o recidiva de la siguiente manera: a. El sujeto recibió AHM durante un mínimo de 6 ciclos y aún seguía dependiendo de las transfusiones (definición en 5b a continuación). b. El paciente presentó progresión de la enfermedad antes del ciclo 6, la cual se define como un incremento ≥50 % de los blastocitos en la médula ósea desde los valores previos al tratamiento hasta valores >5 %, o una reducción ≥2 g/dl de la Hgb con respecto a la concentración previa al tratamiento, con dependencia de transfusiones tras un mínimo de 2 ciclos del AHM. Están permitidos otros tratamientos previos para el SMD como lenalidomida, citarabina, quimioterapia intensiva, hidroxicarbamida, eritropoyetina y otros factores de crecimiento, así como el trasplante de células hematopoyéticas (TCH). 5. Los pacientes deben presentar ya sea: a. Blastocitos en médula ósea >5 % en la aleatorización O b. Dependencia de transfusiones, esto es, haber recibido una transfusión (para el tratamiento de la enfermedad activa) de 2 o más unidades de eritrocitos o plaquetas en las 8 semanas anteriores a la aleatorización. 6. Aclaramiento de creatinina o tasa de filtración glomerular ≥30 mL/min, estimada esta última mediante la fórmula de Cockroft-Gault (C-G) u otras fórmulas de aceptación médica como MDRD (fórmula desarrollada durante el estudio «Modification of Diet in Renal Disease») o la fórmula del grupo CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). 7. Las mujeres en edad fértil no deben estar embarazadas ni en período de lactancia y deben tener un resultado negativo en una prueba de embarazo en la selección. Las mujeres en edad fértil y los hombres con parejas en edad fértil deben aceptar el uso de 2 métodos anticonceptivos muy eficaces y evitar el embarazo durante el tratamiento con guadecitabina, ACDB o QI y durante un mínimo de 3 meses tras finalizar el tratamiento. |
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E.4 | Principal exclusion criteria |
1. Subjects who have been diagnosed as having acute myeloid leukemia (AML) with peripheral blood or bone marrow blasts of ≥20%. 2. Subjects who may still be sensitive to repeated treatment with decitabine or azacitidine such as subjects who had response to prior decitabine or azacitidine treatment, but relapsed >6 months after stopping treatment with these agents. 3. Prior treatment with guadecitabine. 4. Hypersensitivity to decitabine, guadecitabine, or any of their excipients. 5. Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy. 6. Treated with any investigational drug within 2 weeks of the first dose of study treatment. 7. Total serum bilirubin >2.5 ULN (except for subjects with Gilbert's Syndrome for whom direct bilirubin is <2.5×ULN), or liver cirrhosis or chronic liver disease Child-Pugh Class B or C. 8. Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed. 9. Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol. 10. Refractory congestive heart failure unresponsive to medical treatment, active infection resistant to all antibiotics, or advanced non-MDS associated pulmonary disease requiring >2 liters per minute (LPM) oxygen. |
Los sujetos que cumplan alguno de los criterios de exclusión siguientes no podrán participar en el estudio: 1. Sujetos con un diagnóstico de leucemia mielógena aguda (LMA) con blastocitos en médula ósea o sangre periférica ≥20 %. 2. Sujetos que aún podrían ser sensibles a la repetición del tratamiento con decitabina o azacitidina, por ejemplo, aquellos con respuesta al tratamiento previo con estos fármacos, pero que presentaron una recidiva en un plazo >6 meses tras su cese. 3. Tratamiento previo con guadecitabina. 4. Hipersensibilidad a decitabina, guadecitabina o cualquiera de sus excipientes. 5. Segunda neoplasia maligna que precisa tratamiento activo, excepto cáncer de próstata o mama que se encuentra estable o en respuesta con la hormonoterapia. 6. Tratamiento con algún medicamento en investigación en las 2 semanas anteriores a la primera dosis del tratamiento del estudio. 7. Bilirrubina sérica total >2,5 × LSN (excepto en pacientes con síndrome de Gilbert con bilirrubina directa <2,5 × LSN), o cirrosis hepática o hepatopatías de clase B o C según la escala de Child-Pugh. 8. Infección activa conocida por el virus de la inmunodeficiencia humana (VIH), el virus de la hepatitis B (VHB) o el virus de la hepatitis C (VHC). Se permite el estado de portador sano del virus de la hepatitis o un valor bajo de virus de la hepatitis durante el tratamiento con antivirales. 9. Enfermedad mental importante y conocida u otro tipo de trastornos, como alcoholismo, drogodependencia, farmacodependencia o abuso de sustancias, que en opinión del investigador, predispongan al sujeto a un riesgo elevado de incumplimiento del protocolo. 10. Insuficiencia cardíaca congestiva resistente al tratamiento médico, infección activa resistente a todos los antibióticos, o enfermedad pulmonar avanzada no relacionada con el SMD que requiere una cantidad de oxígeno >2 litros por minuto (LPM). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Survival (OS), defined as the number of days from the day the subject was randomized to the date of death (regardless of cause). |
Supervivencia global (SG), definida como el número de días transcurridos entre la fecha de aleatorización del sujeto y la fecha de la muerte (independientemente de la causa). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After randomization, visits will occur on every treatment day. In addition, visits will occur on Days 8, 15, and 22 of the first 2 cycles of therapy, and on Days 1 and 15 of Cycles 3-6. In Cycles >6, only treatment day visits are required, with study-specified assessments required only on Day 1. Additional visits, based on treatment effect and blood counts, may be done at the investigator’s discretion. Subjects will attend a safety follow-up visit after the last study treatment. For subjects who discontinue study treatment before Cycle 6, long-term follow-up visits will occur monthly until 6 months after the start of study treatment and then every 2 months thereafter. For subjects who discontinue study treatment after Cycle 6, long-term follow-up will be every 2 months. |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints - Transfusion independence for any 8 consecutive weeks based on rolling 8-week assessments [number and rate of subjects who are free of transfusions for 8 consecutive weeks (or more) at any time after start of study treatment and who have Hgb of ≥8 g/dL and platelets ≥20×109/L]. - Marrow CR (mCR) based on IWG 2006 criteria with transfusion independence (as defined above). - Survival rate at 1 year after randomization. - Leukemia-free survival defined as the number of days from the day of randomization to the date when BM or peripheral blood (PB) blasts reach ≥20%, or death of any cause. - Number of days alive and out of the hospital (NDAOH). - Disease response including CR, mCR, PR, and HI; including HI with erythroid (HI-E), neutrophil (HI-N), or platelet (HI-P) response, based on IWG 2006 criteria. - Duration of response. - Number of RBC or platelet transfusions (units) over the duration of the study treatment. - Health-related QOL by EQ-5D™ (consisting of the EQ-5D-5L descriptive system and the EQ Visual Analogue Scale [EQ VAS]). - Incidence and severity of adverse events (AEs). - 30- and 60-day all-cause mortality. |
•Independencia de transfusiones durante 8 semanas consecutivas, sobre la base de evaluaciones sucesivas de 8 semanas. Número y proporción de pacientes sin transfusiones durante 8 semanas consecutivas (o más) en cualquier momento tras el inicio del tratamiento del estudio, o con valores de Hgb ≥8 g/dl y plaquetas ≥20 × 109/L. •RC medular (RCm) conforme a los criterios de 2006 del IWG, con independencia de transfusiones (tal y como se ha definido anteriormente). •Tasa de supervivencia 1 año después de la aleatorización. •Supervivencia libre de leucemia, definida como el número de días transcurridos entre la fecha de aleatorización y la fecha en que el valor de los blastocitos en médula ósea (MO) o en sangre periférica (SP) es ≥20 %, o la fecha de la muerte por cualquier causa. •Número de días en que el paciente está vivo y sin hospitalizar (NDVSH). •Respuesta de la enfermedad, que incluye RC, RCm, RP y MH; donde la MH puede ser una respuesta de eritrocitos (MH-E), neutrófilos (MH-N) o plaquetas (MH-P), conforme a los criterios de 2006 del IWG. •Duración de la respuesta. •Número de transfusiones de eritrocitos o plaquetas (unidades) durante el tratamiento del estudio. •CDV relacionada con la salud con el cuestionario EQ-5D™ (constituido por el sistema descriptivo EQ-5D-5L y la escala visual analógica EQ [EQ-EVA]). •Incidencia e intensidad de los acontecimientos adversos (AAs). •Mortalidad por todas las causas a los 30 y 60 días. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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) | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Best Supportive Care only: given according to standard and institutional practice. |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
Korea, Democratic People's Republic of |
United States |
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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
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The primary efficacy endpoint is overall survival (OS), which will be assessed after at least 316 death events have occurred.
The duration of individual subject participation will vary. Subjects may continue to receive treatment for as long as they continue to benefit.
The final study end will be when the last randomized patient has either died, withdrawn from the study, or stopped study treatment. |
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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 | 27 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 27 |