A phase 3 multicenter, randomised, prospective, open-label trial of fixed-duration (12 cycles) venetoclax/ obinutuzumab vs. fixed-duration (15 cycles) venetoclax/ pirtobrutinib vs. MRD-guided venetoclax/ pirtobrutinib in patients with previously untreated chronic lymphocytic leukaemia (CLL)/ small lymphocytic lymphoma (SLL) aiming to establish measurement of individual residual disease for adjustment of treatment duration to improve outcomes (CLL18/MOIRAI)
ESTADO CLÍNICO
Reclutando
FASE/S DEL ENSAYO
Fase III
PATOLOGÍA
Leucemia linfática crónica y otros SLPC, Leucemia mieloide aguda, Trasplante de progenitores hematopoyéticos, Leucemia mieloide crónica, Linfoma, Leucemia
CENTRO INVESTIGADOR
H.U. Infanta Leonor
INVESTIGADOR PRINCIPAL
Jose Angel Hernandez Rivas
CENTRO INVESTIGADOR
H.U. de La Princesa
INVESTIGADOR PRINCIPAL
Javier Loscertales Pueyo
CENTRO INVESTIGADOR
H.U. 12 de Octubre
INVESTIGADOR PRINCIPAL
Javier de la Serna Torroba
CENTRO INVESTIGADOR
H.U. La Paz
INVESTIGADOR PRINCIPAL
Patricia Baltasar Tello
FECHA DE APERTURA
Marzo, 2025
FECHA DE CIERRE
,
CRITERIOS DE INCLUSIÓN
Documented CLL/SLL requiring treatment according to iwCLL criteria with a CLL phenotype cell count >10-2 tracked by flow cytometry at screening.
Adequate bone marrow function as indicated by: - an absolute neutrophil count 1 x 10/l - a hemoglobin value 8.0 g/dL without transfusions during the last 7 days unless directly attributable to CLL/SLL (e.g. bone marrow infiltration) and - a platelet count 25 x 10/l unless due to the CLL/SLL, in this case, platelet count should be 10.000/µl without transfusion during the last 7 days.
Adequate renal function, as indicated by a creatinine clearance 30ml/min calculated according to the MDRD-formula or an equally accurate method (e.g. 24 hr. urine collection)
Adequate liver function as indicated by: - a total bilirubin 2 x the institutional upper limit of normal (ULN) value, and - AST/ ALT 2.5 x the institutional ULN value, unless directly attributable to the patients CLL/SLL or to Gilberts Syndrome.
Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dosage of obinutuzumab), negative testing for hepatitis-C (HCV-RNA PCR) and negative HIV test within 6 weeks prior to registration
Age 18 years
Eastern Cooperative Oncology Group Performance Status (ECOG) performance status
Life expectancy 6 months
Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
Adequate bone marrow function as indicated by: - an absolute neutrophil count 1 x 10/l - a hemoglobin value 8.0 g/dL without transfusions during the last 7 days unless directly attributable to CLL/SLL (e.g. bone marrow infiltration) and - a platelet count 25 x 10/l unless due to the CLL/SLL, in this case, platelet count should be 10.000/µl without transfusion during the last 7 days.
Adequate renal function, as indicated by a creatinine clearance 30ml/min calculated according to the MDRD-formula or an equally accurate method (e.g. 24 hr. urine collection)
Adequate liver function as indicated by: - a total bilirubin 2 x the institutional upper limit of normal (ULN) value, and - AST/ ALT 2.5 x the institutional ULN value, unless directly attributable to the patients CLL/SLL or to Gilberts Syndrome.
Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dosage of obinutuzumab), negative testing for hepatitis-C (HCV-RNA PCR) and negative HIV test within 6 weeks prior to registration
Age 18 years
Eastern Cooperative Oncology Group Performance Status (ECOG) performance status
Life expectancy 6 months
Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
CRITERIOS DE EXCLUSIÓN
Any prior CLL- or SLL-specific therapies, except for corticosteroid treatment administered due to necessary immediate intervention (within the last 10 days before start of study treatment only dose equivalents up to 20 mg prednisolone per day are permitted).
Fertile men or women of childbearing potential unless: - surgically sterile or 2 years after the onset of menopause, or - willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for the required time period thereafter (at least one and up to 18 months after end of study treatment depending of study drug(s) used, see chapter 2.2.2.1 Known risks relevant with all study drugs).
Vaccination with a live vaccine 28 days prior to registration
Use of investigational agents which might interfere with the study drug within 28 days prior to registration
Legal incapacity
Prisoners or subjects who are institutionalized by regulatory or court order
Persons who are in dependence to the sponsor or an investigator
Decompensated auto-immune cytopenia (defined as ongoing drop in hemoglobin (AIHA) or in platelets (ITP) in spite of prednisolone and/or intravenous immunoglobulins treatment).
(Suspicion of) transformation of CLL/SLL (i.e. Richter`s transformation) or central nervous system (CNS) involvement.
(Suspicion of) progressive multifocal leukoencephalopathy (PML).
Malignant neoplasm other than CLL/SLL unless in remission and unlikely to adversely impact on patient´s life expectancy, defined as curatively treated non-melanoma skin cancer or other neoplasias treated curatively 1 year ago, without signs of progression and not currently requiring systemic therapies (with the exception of ongoing anti-hormonal therapy).
Active infection requiring systemic treatment, including HIV, HBV and HCV
Increased risk of bleeding, e.g. due to: - known bleeding disorder - anticoagulant therapy with phenprocoumon or other vitamin K antagonists (anticoagulation with a direct oral Xa or thrombin inhibitor (DOAC) or heparin) is permitted) - major surgery 4 weeks prior to randomization - stroke or intracranial hemorrhage 6 months of randomization
Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4 or any other life-threatening illness, medical condition or organ system dysfunction that in the investigator´s opinion - could compromise the patient`s safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tab-lets or impaired resorption in the gastrointestinal tract)
Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
Fertile men or women of childbearing potential unless: - surgically sterile or 2 years after the onset of menopause, or - willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for the required time period thereafter (at least one and up to 18 months after end of study treatment depending of study drug(s) used, see chapter 2.2.2.1 Known risks relevant with all study drugs).
Vaccination with a live vaccine 28 days prior to registration
Use of investigational agents which might interfere with the study drug within 28 days prior to registration
Legal incapacity
Prisoners or subjects who are institutionalized by regulatory or court order
Persons who are in dependence to the sponsor or an investigator
Decompensated auto-immune cytopenia (defined as ongoing drop in hemoglobin (AIHA) or in platelets (ITP) in spite of prednisolone and/or intravenous immunoglobulins treatment).
(Suspicion of) transformation of CLL/SLL (i.e. Richter`s transformation) or central nervous system (CNS) involvement.
(Suspicion of) progressive multifocal leukoencephalopathy (PML).
Malignant neoplasm other than CLL/SLL unless in remission and unlikely to adversely impact on patient´s life expectancy, defined as curatively treated non-melanoma skin cancer or other neoplasias treated curatively 1 year ago, without signs of progression and not currently requiring systemic therapies (with the exception of ongoing anti-hormonal therapy).
Active infection requiring systemic treatment, including HIV, HBV and HCV
Increased risk of bleeding, e.g. due to: - known bleeding disorder - anticoagulant therapy with phenprocoumon or other vitamin K antagonists (anticoagulation with a direct oral Xa or thrombin inhibitor (DOAC) or heparin) is permitted) - major surgery 4 weeks prior to randomization - stroke or intracranial hemorrhage 6 months of randomization
Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4 or any other life-threatening illness, medical condition or organ system dysfunction that in the investigator´s opinion - could compromise the patient`s safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tab-lets or impaired resorption in the gastrointestinal tract)
Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
DESCRIPCIÓN
The primary objective of the study is to compare the efficacy of MRD-guided Venetoclax/Pirtobrutinib vs fixed-duration (15 cycles) Venetoclax/Pirtobrutinib and MRD-guided Venetoclax/Pirtobrutinib vs. fixed-duration (12 cycles) Venetoclax/Obinutuzumab by measuring progression-free survival (PFS) in patients with previously untreated chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL).
PALABRAS CLAVE
chronic leukemia, chronic lymphocytic leukemia (cll), donor lymphocyte infusion, leukemia, lymphocytic, lymphoma, mrd, small lymphocytic lymphoma
