Resumen

El propósito de este estudio de Fase 3 es evaluar la eficacia y seguridad de luspatercept en comparación con placebo en sujetos con neoplasia mieloproliferativa (MPN) asociada a mielofibrosis (MF) y anemia en terapia concomitante con inhibidor de Janus quinasa 2 (JAK2) que requieren transfusiones de glóbulos rojos (RBC). El estudio se divide en un Período de Selección, una Fase de Tratamiento (que consiste en un Período de Tratamiento Principal Ciego, una Evaluación de Respuesta en el Día 169, un Período de Tratamiento de Extensión Ciego y un Período de Tratamiento de Extensión Abierto) y un Período de Seguimiento Postratamiento. Tras la Evaluación de Respuesta en el Día 169, los sujetos que no mostraron beneficio clínico tendrán la opción de develar el ciego. Los sujetos que recibieron placebo durante el Período de Tratamiento Principal Ciego tendrán la oportunidad de cruzar al Período de Tratamiento de Extensión Abierto y recibir luspatercept.

Descripción detallada

Medicamentos y Procedimientos Concomitantes Permitidos * Los sujetos reciben un inhibidor de JAK2 para el tratamiento de la MF asociada a MPN aprobado en el país donde se realiza el estudio. Los inhibidores de JAK2 deben utilizarse según su prospecto correspondiente y según prescripción como parte de la terapia estándar de atención del sujeto, tal como lo prescribió su médico antes del ingreso al estudio. * La mejor atención de soporte (BSC) incluye, entre otros, tratamiento con transfusiones (p. ej., GR, plaquetas, sangre total), terapia de quelación de hierro (ICT), terapia antibiótica, antiviral y/o antimicótica, y apoyo nutricional según sea necesario. * Los factores estimulantes de colonias de granulocitos (es decir, G-CSF, factor estimulante de colonias de granulocitos y macrófagos \[GM-CSF\]) están permitidos únicamente en casos de fiebre neutropénica o cuando esté clínicamente indicado según el prospecto del producto. * La terapia antitrombótica profiláctica está permitida. * La trombopoyetina y las transfusiones de plaquetas están permitidas. * El tratamiento con corticosteroides sistémicos está permitido para afecciones no hematológicas, siempre que el sujeto reciba una dosis constante equivalente a ≤ 10 mg de prednisona durante el estudio. * La administración de vacunas atenuadas (p. ej., vacuna contra la influenza) está permitida si está clínicamente indicada según el criterio del Investigador. * La terapia de quelación de hierro (ICT) debe utilizarse según el prospecto del producto. Si el prospecto lo permite, la dosis de ICT debe ser estable durante al menos las primeras 24 semanas del producto en investigación (PI). El inicio de la ICT dentro de las primeras 24 semanas del PI debe estar clínicamente indicado para tratar un evento adverso (EA). Medicamentos Concomitantes Prohibidos Los siguientes medicamentos concomitantes están específicamente excluidos durante el tratamiento del estudio: * Agentes/terapias citotóxicos, quimioterápicos, dirigidos o en investigación (excluyendo la terapia con inhibidor de JAK2) * Azacitidina, decitabina u otros agentes hipometilantes * Lenalidomida, talidomida y pomalidomida * Agentes estimulantes de la eritropoyesis (AEE) y otros factores de crecimiento hematopoyético para GR (p. ej., IL-3) * Hidroxiurea u otros agentes alquilantes * Andrógenos (a menos que se administren para tratar el hipogonadismo) * Retinoides orales (los retinoides tópicos están permitidos) * Trióxido de arsénico * Interferón * Anagrelida * Corticosteroides sistémicos a una dosis equivalente a \> 10 mg de prednisona * Productos en investigación para el tratamiento de la MF asociada a MPN

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Subjects must satisfy the following criteria to be randomized in the study:
\- Subject is ≥18 years of age at the time of signing the ICF.
Subject has a diagnosis of PMF according to the 2016 World Health Organization (WHO) criteria or diagnosis of post-ET or post-PV MF according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report.
Subject is requiring RBC transfusions as defined as:.
i) Average RBC-transfusion frequency: 4 to 12 RBC units/12 weeks immediately up to randomization. There must be no interval \> 6 weeks (42 days) without ≥ 1 RBC transfusion.
ii) RBC transfusions are scored in determining eligibility when given for treatment of:.
A. Symptomatic (ie, fatigue or shortness of breath) anemia with a pretransfusion Hgb ≤ 9.5 g/dL or.
B. Asymptomatic anemia with a pretransfusion Hgb ≤ 7 g/dL.
iii) RBC transfusions given for worsening of anemia due to bleeding or infections are not scored in determining eligibility.
\- Subjects on continuous (eg, absent of dose interruptions lasting ≥ 2 consecutive weeks) JAK2 inhibitor therapy as approved in the country of the study site for the treatment for MPN-associated MF as part of their standard-of-care therapy for at least 32 weeks, on stable daily dose for at least 16 weeks immediately up to the date of randomization and anticipated to be on a stable daily dose of that JAK2 inhibitor for at least 24 weeks after randomization.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
A female of childbearing potential (FCBP) for this study is defined as a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (eg, has had menses at any time in the preceding 24 consecutive months). Females of childbearing potential (FCBP)participating in the study must:.
i) Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the study, and after end of IP. This applies even if the subject practices true abstinence\* from heterosexual contact.
ii) Either commit to true abstinence\* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception\*\* without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) after discontinuation of study therapy.
\- Male subjects must: Practice true abstinence\* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential\*\* while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy.
i) True abstinence is acceptable when it is in line with the preferred and usual lifestyle of the subject. \[Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.\].
ii) Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception: Oral, Intravaginal, Transdermal; Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral, Injectable hormonal contraception, Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.
Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
Subject is willing and able to adhere to the study visit schedule and other protocol requirements including the use of the electronic patient reported outcomes device.

Criterios de exclusión

The presence of any of the following will exclude a subject from randomization:.
Subject with anemia from cause other than MPN-associated MForJAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration).
Subject use of hydroxyurea, immunomodulatory compounds such as pomalidomide, thalidomide, ESAs, androgenic steroids or other drugs with potential effects on hematopoiesis ≤ 8 weeks immediately up to the date of randomization.
i) Systemic corticosteroids are permitted for nonhematological conditions providing the subject is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 4 weeks immediately up to randomization.
ii) Iron chelation therapy (ICT) is permitted providing the subject is receiving a stable dose for the 8 weeks immediately up to randomization.
\- Subject with any of the following laboratory abnormalities at screening:.
i) Neutrophils: \< 1 x 10\^9/L.
ii) White blood count (WBC): \> 100 x 10\^9/L.
iii) Platelets: the lowest allowable level as approved for the concomitant JAK2 inhibitor but not \< 25 x 10\^9/L or \> 1000 x 10\^9/L.
iv) Peripheral blood myeloblasts:\> 5%.
v) Estimated glomerular filtration rate:\< 30 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease \[MDRD\] formula) or nephrotic subjects (eg, urine albumin-to-creatinine ratio \> 3500 mg/g).
vi) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT):\> 3.0 x upper limit of normal (ULN).
vii) Direct bilirubin: ≥ 2 x ULN.
A. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (eg, ineffective erythropoiesis).
Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, that is not resolved at the time of randomization.
Subject with prior history of malignancies, other than disease under study, unless the subject has been free of the disease for ≥ 3 years. However, subject with the following history/concurrent conditions is allowed:.
i) Basal or squamous cell carcinoma of the skin.
ii) Carcinoma in situ of the cervix.
iii) Carcinoma in situ of the breast.
iv) Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[TNM\] clinical staging system).
Subject with prior hematopoietic cell transplant or subject anticipated to receive a hematopoietic cell transplant during the 24 weeks from the date of randomization. 7. Subject with stroke, myocardial infarction, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the date of randomization.
Subject with major surgery within 2 months up to the date of randomization. Subject must have completely recovered from any previous surgery immediately up to the date of randomization.
Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of packed red cells) in the last 6 months prior to the date of randomization.
Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction \< 35%.
Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
Subject with known human immunodeficiency virus (HIV), evidence of active Hepatitis B (HepB) as demonstrated by the presence of Hepatitis B surface antigen (HBsAg) and/or positive for Hepatitis B virus DNA (HBVDNA-positive), and/or evidence of active Hepatitis C (HepC) as demonstrated by a positive Hepatitis C virus RNA (HCV-RNA) test of sufficient sensitivity.
Subject with prior therapy of luspatercept or sotatercept.
Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product.
Pregnant or breastfeeding females.
Subject participation in any other clinical protocol or investigational trial that involves use of experimental therapy (including investigational agents) and/or therapeutic devices within 30 days or for investigational agents within five half-lives, whichever comes later, immediately up to the date of randomization.
Subject with any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study or places the subject at unacceptable risk if he/she were to participate in the study. 18.Subject with any condition or concomitant medication that confounds the ability to interpret data from the study.

Estudio de Fase 3, doble ciego, aleatorizado para comparar la eficacia y seguridad de luspatercept (ACE-536) versus placebo en sujetos con mielofibrosis asociada a neoplasia mieloproliferativa en terapia concomitante con inhibidor JAK que requieren transfusiones de glóbulos rojos

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

ACE-536

Placebo

Ubicaciones

Local Institution - 172

Hospital Italiano de La Plata

Hospital Italiano de Buenos Aires

Patrocinadores