Un estudio de CA-4948 en pacientes con neoplasias malignas hematológicas recidivantes o refractarias
Linfoma TakeAim: un ensayo abierto de aumento de dosis y expansión de dosis que evalúa la seguridad, la farmacocinética, la farmacodinámica y la actividad clínica de CA-4948 administrado por vía oral en pacientes con neoplasias malignas hematológicas recidivantes o refractarias
This is a multi-center, open-label study to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib alone or in combination with ibrutinib in adult participants with relapsed or refractory (R/R) hematologic malignancies.
This trial will be completed in four parts. In Part A1, emavusertib will be evaluated first in a dose escalating monotherapy setting to establish the safety and tolerability (complete). In Part A2, emavusertib will be evaluated in combination with ibrutinib at 560 milligrams (mg) once daily (QD) or 420 mg QD as indicated by disease (Part A2 complete).
Part B will comprise 2 cohorts to assess safety and efficacy of emavusertib in combination with ibrutinib in participants with R/R primary central nervous system lymphoma (PCNSL) who have directly progressed on a bruton tyrosine kinase inhibitor (BTKi). In this part of the study, emavusertib will be dosed at 100 mg or 200 mg twice daily (BID) in combination with ibrutinib in 28-day treatment cycles.
Part C will comprise 3 treatment arms in the second-line setting to assess the efficacy and safety of emavusertib monotherapy, ibrutinib monotherapy, and emavusertib in combination with ibrutinib in participants with R/R PCNSL who are naïve to BTKi treatment. In this part of the study, eligible second-line participants with R/R PCNSL who are naïve to BTKi treatment will be randomized 1:1:1 to 1 of 3 treatment arms: (1) emavusertib 200 mg BID, (2) ibrutinib 560 mg QD, or (3) emavusertib 200 mg BID in combination with ibrutinib 560 mg QD.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 2
- Fase 1
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Ahmed Hamdy, MD
- Número de teléfono: 617-503-6500
- Correo electrónico: clinicaltrials@curis.com
Ubicaciones de estudio
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Prague, Chequia
- Reclutamiento
- Všeobecná fakultní nemocnice v Praze
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Barcelona, España
- Reclutamiento
- University Hospital Vall d'Hebron
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Madrid, España
- Reclutamiento
- MD Anderson Cancer Center Madrid
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Seville, España
- Reclutamiento
- Hospital Universitario Virgen del Rocio
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Arizona
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Phoenix, Arizona, Estados Unidos, 85013
- Reclutamiento
- St. Joseph's Hospital and Medical Center
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Phoenix, Arizona, Estados Unidos, 85054
- Terminado
- Mayo Clinic
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California
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Duarte, California, Estados Unidos, 91010
- Reclutamiento
- City of Hope
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Santa Monica, California, Estados Unidos, 90404
- Reclutamiento
- Providence St. John's Health Center
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Santa Monica, California, Estados Unidos, 90404
- Retirado
- UCLA Department of Medicine - Hematology/Oncology
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Connecticut
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New Haven, Connecticut, Estados Unidos, 06510
- Terminado
- Smilow Cancer Hospital at Yale-New Haven
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Florida
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Jacksonville, Florida, Estados Unidos, 32224
- Reclutamiento
- Mayo Clinic
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Illinois
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Chicago, Illinois, Estados Unidos, 60611
- Reclutamiento
- Northwestern Memorial Hospital
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Massachusetts
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Boston, Massachusetts, Estados Unidos, 02215
- Reclutamiento
- Dana Farber Cancer Institute
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Minnesota
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Rochester, Minnesota, Estados Unidos, 55905
- Reclutamiento
- Mayo Clinic
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Nebraska
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Omaha, Nebraska, Estados Unidos, 68198
- Reclutamiento
- Fred and Pamela Buffett Cancer Center
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New Jersey
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Hackensack, New Jersey, Estados Unidos, 07601
- Terminado
- Hackensack University Medical Center
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New York
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Buffalo, New York, Estados Unidos, 14263
- Reclutamiento
- Roswell Park Comprehensive Cancer Center
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New York, New York, Estados Unidos, 10065
- Reclutamiento
- Memorial Sloan Kettering Cancer Center
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New York, New York, Estados Unidos, 10032
- Retirado
- Columbia University Irving Medical Center
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New York, New York, Estados Unidos, 10029
- Reclutamiento
- Mt Sinai
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North Carolina
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Durham, North Carolina, Estados Unidos, 27710
- Reclutamiento
- Duke University Medical Center, Duke Cancer Center
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Ohio
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Cleveland, Ohio, Estados Unidos, 44195
- Reclutamiento
- Cleveland Clinic
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Oregon
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Portland, Oregon, Estados Unidos, 97225
- Reclutamiento
- Providence Neurological Specialties West
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Pennsylvania
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Philadelphia, Pennsylvania, Estados Unidos, 19104
- Terminado
- Hospital of the University of Pennsylvania
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Pittsburgh, Pennsylvania, Estados Unidos, 15232
- Reclutamiento
- UPMC Hilman Cancer Center
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Tennessee
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Knoxville, Tennessee, Estados Unidos, 37920
- Terminado
- University of Tennessee Medical Center
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Texas
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Dallas, Texas, Estados Unidos, 75235
- Activo, no reclutando
- UT Southwestern Medical Center
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Houston, Texas, Estados Unidos, 77030
- Reclutamiento
- The University of Texas MD Anderson Cancer Center
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Utah
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Salt Lake City, Utah, Estados Unidos, 84112
- Reclutamiento
- Huntsman Cancer Institute, University of Utah
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Washington
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Seattle, Washington, Estados Unidos, 98195
- Reclutamiento
- University of Washington Medical Center
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Seattle, Washington, Estados Unidos, 98104
- Terminado
- Swedish Cancer Institute
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Bordeaux, Francia
- Reclutamiento
- Institut Bergonie
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Marseille, Francia
- Reclutamiento
- Hopital de la Timone
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Paris, Francia
- Reclutamiento
- Hospital Pitie Salpetriere
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Paris, Francia
- Reclutamiento
- Institut Curie Hospital
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Beersheba, Israel
- Reclutamiento
- Hematology Department Soroka UMC / Heanatology Department
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Haifa, Israel
- Reclutamiento
- Rambam Medical Center
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Jerusalem, Israel
- Reclutamiento
- Hadassah Medical Center / Ein-Carem
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Cuneo, Italia
- Reclutamiento
- Università di Torino Croce e Carle
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Florence, Italia
- Reclutamiento
- SODc Ematologia Azienda Ospedaliera Universitaria Careggi
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Meldola, Italia
- Reclutamiento
- IRST - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
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Milan, Italia
- Reclutamiento
- IRCCS San Raffaele Scientific Institute
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Gdansk, Polonia
- Reclutamiento
- Uniwersyteckie Centrum Kliniczne Osrodek Badan Klinicznych Wczesnych Faz
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Krakow, Polonia
- Retirado
- Oddzial Kliniczny Hematologii
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Warsaw, Polonia
- Reclutamiento
- NarodowyInstytutu Onkologii im. Marii Sklodowskiej-Curie-Panstwowy Instytutu Badawczy
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
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Males and females greater than or equal to 18 years of age
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Life expectancy of at least 3 months
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Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2
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Histopathologically confirmed diagnosis of PCNSL (medical record is acceptable). Cerebral biopsies are not required if imaging reveals typical images of PCNSL.
- Participants with parenchymal lesions must have unequivocal evidence of disease progression (e.g., presence of at least 1 measurable target lesion [≥ 10 millimeters (mm) and ≤ 40 mm in the longest diameter on brain magnetic resonance imaging [MRI] or head computed tomography [CT] on imaging within 28 days prior to Cycle 1 Day 1]). In cases where the tumor size is smaller but still measurable and located at a critical central nervous system (CNS) location, disabling the participant and/or causing symptoms, this participant may be eligible following a discussion with the Sponsor Medical Monitor.
- For participants limited to leptomeningeal involvement, cerebrospinal fluid (CSF) analysis (cytology and/or flow cytometry) with or without additional imaging (MRI) of the spine as clinically indicated is required to document abnormal cells within 28 days prior to Cycle 1 Day 1.
Exclusion Criteria for Part B and Part C
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Participants with only intraocular PCNSL without brain lesion or CSF involvement, T-cell lymphoma, systemic presence of lymphoma, or non-CNS lymphoma metastatic to the CNS
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Evidence of systemic lymphoma. This must be demonstrated by a positron emission tomography (PET) scan (or CT scan with contrast if applicable) of the chest, abdomen, and pelvis at Screening (testicular ultrasound may be considered to exclude a testicular lymphoma disseminated to the brain).
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Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) or prior history of systemic lymphoma, unless the participant has been free of the disease for ≥ 3 years.
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Active malignancy other than PCNSL requiring systemic therapy
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Previous BTKi treatment (Part C only).
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History of Grade ≥ 3 rhabdomyolysis without complete recovery
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Requirement for urgent therapy due to uncontrolled tumor mass/edema effects.
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Received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1.
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Received prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1; allogeneic hematopoietic stem cell transplant (HSCT) within 60 days prior to Cycle 1 Day 1; or had clinically significant graft-versus-host disease (GVHD) requiring ongoing up-titration of immunosuppressive medications prior to Screening (with the exception of a BTKi for Part B only).
Note: The use of a stable or tapering dose of immunosuppressive therapy post-HSCT and/or topical steroids for ongoing skin GVHD is permitted with Sponsor Medical Monitor approval
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Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1 (with the exception of ibrutinib or other BTKi for Part B only, which may be continued until the day before Cycle 1 Day 1)
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Prior history of hypersensitivity or anaphylaxis to emavusertib, ibrutinib or any of their excipients.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: No aleatorizado
- Modelo Intervencionista: Asignación Secuencial
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: Emavusertib (CA-4948) dose escalation
Part A1: Dose-level cohorts with up to approximately 6 participants each will be used to define the Maximum Tolerated Dose (MTD) for emavusertib. |
Emavusertib will be provided as a tablet dosage form to be taken BID.
Otros nombres:
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Experimental: Emavusertib (CA-4948) and ibrutinib dose escalation
Part A2: Evaluate escalating dose levels of oral emavusertib in combination with 560 mg QD or 420 mg QD of oral ibrutinib. The starting dose of emavusertib to be used in combination will be 200 mg BID. It is anticipated that 12 to 20 participants at a potential dose level will be required to establish optimal combination dosing. |
Emavusertib will be provided as a tablet dosage form to be taken BID.
Otros nombres:
Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD. |
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Experimental: Emavusertib (CA-4948) and ibrutinib dose expansion
In two Expansion Cohorts (Part B), emavusertib in combination with ibrutinib will be administered in participants with R/R PCNSL who have progressed on a BTKi. In Cohort 1, emavusertib 100 mg BID will be administered with ibrutinib 560 mg QD consecutively in 28-day treatment cycles. In Cohort 2, emavusertib 200 mg BID will be administered with ibrutinib 560 mg QD consecutively in 28-day treatment cycles. |
Emavusertib will be provided as a tablet dosage form to be taken BID.
Otros nombres:
Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD. |
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Experimental: Emavusertib (CA-4948) and ibrutinib
In this part of the study (Part C), eligible second-line participants with R/R PCNSL who are naïve to BTKi treatment will receive 1 of 3 treatment arms: (1) emavusertib 200 mg BID, (2) ibrutinib 560 mg QD, or (3) emavusertib 200 mg BID in combination with ibrutinib 560 mg QD. Treatments will be administered continuously in 28-day treatment cycles. |
Emavusertib will be provided as a tablet dosage form to be taken BID.
Otros nombres:
Ibrutinib will be provided as a tablet or capsule dosage form to be taken QD. |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Parte B: Tasa de respuesta general (ORR) en participantes con R/R PCNSL
Periodo de tiempo: 18 meses
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18 meses
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Parte C: ORR en participantes con R/R PCNSL
Periodo de tiempo: 18 meses
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18 meses
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Part A: To determine the safety and tolerability of emavusertib as a monotherapy and in combination with ibrutinib: dose-limiting toxicity (DLT)
Periodo de tiempo: 12 months
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The number of participants with a dose-limiting toxicity (DLT) in the first treatment cycle |
12 months
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Part A: Maximum tolerated dose (MTD) of emavusertib as a monotherapy and in combination with ibrutinib measured by dose-limiting toxicities (DLTs)
Periodo de tiempo: 12 months
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MTD determined by the highest dose level studied at which fewer than 2 out of 6 subjects (<33%) experience a dose limiting toxicity. |
12 months
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Part A: Recommended Phase 2 Dose (RP2D) of emavusertib as a monotherapy and in combination with ibrutinib based on overall tolerability data
Periodo de tiempo: 12 months
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RP2D selected based on overall tolerability data from all participants treated at different dose levels and will not exceed the MTD. |
12 months
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by AUC
Periodo de tiempo: 24- 66 months
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Area Under the concentration-time curve (AUC) |
24- 66 months
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Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmax
Periodo de tiempo: 24- 66 months
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Maximum plasma concentration (Cmax) |
24- 66 months
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Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Cmin
Periodo de tiempo: 24- 66 months
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Minimum plasma concentration (Cmin) |
24- 66 months
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Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by Tmax
Periodo de tiempo: 24- 66 months
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Time to maximum plasma concentration (Tmax) |
24- 66 months
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Parts A, B and C: Pharmacokinetic (PK) profile of emavusertib and ibrutinib measured by plasma terminal half-life
Periodo de tiempo: 24- 66 months
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Plasma terminal elimination half-life (T 1/2) |
24- 66 months
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Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by ORR
Periodo de tiempo: 24- 36 months
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Assessed by ORR |
24- 36 months
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Parts A, B and C: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib and ibrutinib as monotherapy measured by duration of response (DOR)
Periodo de tiempo: 24- 66 months
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Assessed by DOR |
24- 66 months
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Part A: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib measured by disease control rate (DCR)
Periodo de tiempo: 24- 36 months
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Assessed by DCR |
24- 36 months
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Parts A, B and C: To assess efficacy of emavusertib as a monotherapy and in combination with ibrutinib and ibrutinib as monotherapy measured by progression free survival (PFS)
Periodo de tiempo: 24- 66 months
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Assessed by PFS |
24- 66 months
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Parts A, B and C: To assess efficacy of emavusertib as a monotherapy, in combination with ibrutinib and ibrutinib as monotherapy measured by overall survival (OS)
Periodo de tiempo: 24 - 66 months
|
Assessed by OS |
24 - 66 months
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Parts B and C: To assess the safety and tolerability of emavusertib as monotherapy, ibrutinib as monotherapy and emavusertib in combination with ibrutinib in participants with R/R PCNSL
Periodo de tiempo: up to 66 months
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Measured by the number of participants with treatment-emergent adverse events (TEAEs) and treatment-related adverse events |
up to 66 months
|
Colaboradores e Investigadores
Patrocinador
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
- Enfermedades del sistema inmunológico
- Neoplasias
- Linfoma
- NHL
- Linfoma No Hodgkin
- Ibrutinib
- Trastornos linfoproliferativos
- Trastornos inmunoproliferativos
- Enfermedades linfáticas
- PCNSL
- Linfoma primario del SNC
- IRAK4
- MYD88
- Linfoma del sistema nervioso central (SNC) en recaída/refractario
- Linfoma sistémico con linfoma concurrente del SNC
- Linfoma sistémico con antecedentes de linfoma del SNC tratado
- Inhibidor de la tirosina quinasa de Bruton (BTKI)
Términos MeSH relevantes adicionales
- Procesos Patológicos
- Neoplasias por sitio
- Atributos de la enfermedad
- Neoplasias por tipo histológico
- Enfermedades hematológicas
- Condiciones Patológicas, Signos y Síntomas
- Enfermedades hemic y linfáticas
- Neoplasias
- Reaparición
- Neoplasias Hematológicas
- Linfoma
- Linfoma No Hodgkin
- Trastornos linfoproliferativos
- Enfermedades del sistema inmunológico
- Enfermedades linfáticas
- Trastornos inmunoproliferativos
- ibrutinib
- CA-4948
Otros números de identificación del estudio
- CA-4948-101
- 2024-513312-95-00 (Ctis)
- 2022-000891-20 (Número EudraCT)
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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