Resumen

La mielofibrosis (MF) es una enfermedad de la médula ósea que afecta los tejidos hematopoyéticos del organismo. La MF altera la producción normal de células sanguíneas, causando una cicatrización extensa en la médula ósea. Esto conduce a anemia grave, debilidad, fatiga y esplenomegalia. El objetivo de este estudio es evaluar la seguridad y tolerabilidad de ABBV-744, administrado solo o en combinación con ruxolitinib o navitoclax, en participantes adultos con MF. ABBV-744 es un fármaco en investigación que se está desarrollando para el tratamiento de la MF. El estudio tiene 4 segmentos: A, B, C y D. En el Segmento A se identifica el régimen de dosificación seguro de ABBV-744 y luego se administra solo como monoterapia. En los Segmentos B, C y D se administran terapias combinadas de ABBV-744 con ruxolitinib o navitoclax. Se incluirán participantes adultos con diagnóstico de MF. Se prevé inscribir aproximadamente 130 participantes en 60 centros en todo el mundo. En el Segmento A, los participantes recibirán diferentes dosis y esquemas del comprimido oral de ABBV-744 para identificar el régimen de dosificación seguro. Se inscribirán participantes adicionales con el régimen de monoterapia identificado. En el Segmento B, los participantes recibirán ruxolitinib oral y ABBV-744 se administrará como terapia "complementaria". En el Segmento C, los participantes recibirán ABBV-744 y navitoclax oral. En el Segmento D, los participantes recibirán ABBV-744 y ruxolitinib. Los participantes recibirán el tratamiento hasta la progresión de la enfermedad o hasta que no puedan tolerar los fármacos del estudio. Es posible que la carga del tratamiento para los participantes en este ensayo sea mayor que con su tratamiento estándar. Los participantes asistirán a visitas regulares en un hospital o clínica. El efecto del tratamiento se evaluará mediante valoraciones médicas, análisis de sangre y médula ósea, seguimiento de efectos secundarios y cuestionarios.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Laboratory values indicative of adequate bone marrow, renal, and hepatic function meeting protocol criteria.
Completion of the Myelofibrosis System Assessment Form (MFSAF) on at least 4 out of the 7 days prior to Day 1 with at least 2 symptoms with a score \>=3 or a total score of \>=10.
Documented diagnosis of intermediate or high-risk primary myelofibrosis (PMF), post-polycythemia vera MF (PPV-MF) or post-essential thrombocytopenia MF (PET-MF) as defined by the World Health Organization (WHO).
Eastern Cooperative Oncology Group (ECOG) Performance Status of \<= 2.
Intermediate - 2, or High-Risk disease as defined by the Dynamic International Prognostic Scoring System (For Segment A only, Intermediate - 1 with palpable splenomegaly \>=5 centimeters \[cm\] below costal margin are also eligible).
Splenomegaly defined as spleen palpation measurement \>= 5 cm below costal margin or spleen volume \>= 450 cubic cms as assessed by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scan (for Segments A and C, baseline spleen assessment must be obtained \> 7 days after discontinuation of most recent Myelofibrosis (MF) therapy. If possible, this assessment should occur within 10 days of Cycle 1 Day 1).
Segment-Specific Prior Therapy Criteria:
Segment A:
Prior exposure to one or more Janus Kinase inhibitors (JAKi),\[the most recent of which was discontinued \> 14 days prior to Cycle 1 Day 1\] and are intolerant, resistant, refractory or lost response to the JAKi.
Segment B:
Currently receiving ruxolitinib AND
Willingness to reduce ruxolitinib dose (if on a higher dose); and on a stable dose for 14 days or longer prior to Cycle 1 Day 1; AND
At least one of the following criteria (a, b, or c):
\>= 24 weeks duration of current ruxolitinib course, with evidence of disease that is resistant, refractory, or has lost response to ruxolitinib therapy;
\< 24 weeks duration of current ruxolitinib course with documented resistance, refractories, or loss of response, as defined by any of the following:
Appearance of new splenomegaly that is palpable to at least 5 cm below the left costal margin (LCM), in participants with no evidence of splenomegaly prior to the initiation of ruxolitinib.
\>=100% increase in the palpable distance below the LCM, in participants with measurable spleen distance 5 - 10 cm prior to the initiation of ruxolitinib.
\>=50% increase in the palpable distance below the LCM, in participants with measurable spleen \> 10 cm prior to the initiation of ruxolitinib.
A spleen volume increase \>= 25% (as assessed by MRI or CT) in participants with a spleen volume assessment available prior to the initiation of ruxolitinib.
Prior treatment with ruxolitinib for \>= 28 days complicated by any of the following:
Development of red blood cell transfusion requirement (at least 2 units/month for 2 months).
Grade \>= 3 adverse events of neutropenia and/or anemia while on ruxolitinib treatment, with improvement or resolution upon dose reduction.
Segment C:
Prior exposure to one or more JAKi (the most recent of which was discontinued \> 14 days prior to Cycle 1 Day 1), and are intolerant, resistant, refractory or lost response to the JAKi.

Criterios de exclusión

Segment-Specific Prior Therapy Criteria:
Segment A:
Prior exposure to one or more Bromodomain and Extra-Terminal (BET) inhibitors.
Segment B:
Prior exposure to one or more BET inhibitors.
Segment C:
Prior exposure to one or more BET inhibitors and/or any B-Cell Lymphoma 2 (BCL)-2 and/or BCL- XL inhibitor, including navitoclax.
Segment D:
Prior exposure to JAKi and/or any BET inhibitor.

Estudio de fase 1b de ABBV-744 en monoterapia o en combinación con ruxolitinib o navitoclax en sujetos con mielofibrosis

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

ABBV-744

Navitoclax

Ruxolitinib

Ubicaciones

Hospital Universitario Austral /ID# 228909

Hospital Italiano de Buenos Aires /ID# 226945

Patrocinadores