Chronic Lymphocytic Leukemia MedDRA version: 21.0 Level: LLT Classification code 10008956 Term: Chronic lymphatic leukaemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: Gazyvaro 1000 mg
Product Code: [NA]
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Obinutuzumab
CAS Number: 949142-50-1
Current Sponsor code: NA
Other de
Sponsors
FONDAZIONE GIMEMA (GRUPPO ITALIANO MALATTIE EMATOLOGICHE DELL' ADULTO) FRANCO MANDELLI ONLUS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients older than18 years and 65 years or less. 2. Diagnosis of CLL meeting the iwCLL 2018 criteria. 3. Total CIRS 30 ml/min [Cockcroft-Gault]) and ECOG performance status of 0-1. 4. No prior treatment. 5. Patients with unmutated IGHV, and, or TP53 mutation assessed by an ERIC certified laboratory, and, or deletion 17p assessed by FISH analysis (Appendix N). 6. Active disease meeting at least 1 of the iwCLL 2018 criteria for treatment requirement. 7. Adequate hematologic parameters unless due to disease under study: • Absolute neutrophil count (ANC) =1.0 x 109/L unless neutropenia is clearly due to disease under study (per investigator discretion) • Platelet count = 75,000/mm3 - OR - Platelet count = 20,000/mm3 if thrombocytopenia is clearly due to disease under study (per investigator discretion) • Hemoglobin =9.0 g/dL unless anemia is clearly due to marrow involvement of CLL (per investigator discretion) 8. Adequate renal and hepatic function, per laboratory reference range at Screening as follows: • AST/SGOT, ALT/SGPT =2.0 x ULN • Total bilirubin =1.5 x ULN unless considered secondary to Gilbert’s syndrome, in which case =3 x ULN 9. QT-interval corrected according to Fridericia’s formula (QTcF) =450 milliseconds (ms). 10. For females of childbearing potential, a negative serum pregnancy test within 7 days of study treatment. 11. For female patients of childbearing potential, agreement to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [=65 years) yes F.1.3.1 Number of subjects for this age range 4
Exclusion criteria
Exclusion criteria: 1. Any significant concurrent, uncontrolled medical condition or organ system dysfunction and laboratory abnormality or psychiatric disease, which, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk or prevent the subject from signing the informed consent form. 2. Known active histological transformation from CLL to an aggressive lymphoma (i.e., Richter’s transformation or pro-lymphocytic leukemia). 3. Known central nervous system involvement. 4. Active malignancy or systemic therapy for another malignancy within 3 years Except: • Malignancies surgically treated with curative intent and with no known active disease present for = 3 years before randomization • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease • Adequately treated cervical carcinoma in situ without evidence of disease • Surgically/adequately treated low grade, early stage localized prostate cancer without evidence of disease 5. Co-morbidities: • Uncontrolled autoimmune hemolytic anemia or thrombocytopenia • Any uncontrolled illness that, in the opinion of the investigator, would preclude administration of study therapy. • History of stroke or intracranial hemorrhage within 180 days before first dose of study drug. • History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention due to thrombocytopenia or inherited or acquired bleeding disorders due to deficiency or functional abnormality of any coagulation proteins. • History of significant cardiovascular disease, defined as: a. Congestive heart failure greater than New York Heart Association (NYHA) class II according to the NYHA functional classification. b. Unstable angina or myocardial infarction with 6 months of enrollment. c. Serious cardiac arrhythmia or clinically significant ECG abnormality: corrected QT wave (QTcF) > 480 msec based on the Fridericia's formula or other ECG abnormalities including second-degree atrioventricular block type II, third-degree atrioventricular block. Participants who have a pacemaker will be allowed on study despite ECG abnormalities or the inability to calculate the QTc. • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1. • History of tuberculosis within the last five years or recent exposure to tuberculosis equal to or less than 6 months. • History of progressive multifocal leukoencephalopathy (PML). • History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection: I. Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to take appropriate anti-viral prophylaxis as indicated and undergo monthly DNA testing. II. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. • Inadequate renal function: CrCl < 30 mL/min. • Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis. • History of severe allergic or anaphylactic reactions
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate in young CLL patients with an adverse biologic profile the following co-primary objectives: 1.The benefit of front-line therapy with venetoclax and obinutuzumab (VenObi) in terms of rate of patients with uMRD by ASO-PCR in the PB and BM measured at the end of combination therapy (EOCT month 9). 2.The benefit of adding Zanubrutinib to Venetoclax (VenZan) in terms of rate of patients with uMRD by ASO-PCR in the PB and BM in patients with residual disease at the EOCT with VenObi (month 21).;Secondary Objective: 1)The benefit of front-line therapy with venetoclax and obinutuzumab (VenObi) in terms of rate of patients with uMRD by flow-cytometry at the end of combination therapy (EOCT month 9). 2)The benefit of treatment with VenObi+Ven in terms of rate of patients with uMRD, L-MRD and H-MRD by: a) ASO-PCR b)Flow-cytometry. 3)The benefit of treatment with VenObi+VenZan in terms of rate of patients with uMRD, L-MRD and H-MRD by: a)ASO-PCR b)Flow-cytometry 4)Rate of patients with uMRD according to the baseline clinical and the biologic characteristics of CLL 5)Progression Free Survival (PFS) 6) Overall Survival (OS) 7)Survival outcomes (OS and PFS) according to the: a)levels of MRD b)response c)treatment after VenObi d)the clinical and the biologic characteristics of CLL 8)The benefits on the hematological improvement of treatment with VenObi+Ven or VenObi+VenZan. 9)The toxicity profile of treatment.;Primary end point(s): To evaluate in young CLL patients with an adverse biologic profile: 1. The benefit of front-line therapy with Venetoclax and Obinutuzumab (VenObi) in terms of rate of patients with uMRD by ASO-PCR in the PB and BM measured at the end of combination therapy (EOCT month 9). 2. The benefit of adding Zanubrutinib to Venetoclax (VenZan) in terms of rate of patients with uMRD by ASO-PCR in the PB and BM in patients with residual disease at the EOCT with VenObi (month 21).;Timepoint(s) of evaluation of this end point: | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. The benefit of front-line therapy with Venetoclax and Obinutuzumab (VenObi) in terms of rate of patients with uMRD by flow-cytometry in the PB and BM measured at the end of combination therapy (EOCT month 9). 2. The benefit of treatment with VenObi+Ven in terms of rate of patients with uMRD, L-MRD and H-MRD in the PB and BM at month 15, 21, 27, 33, 36 by: a. ASO-PCR b. Flow-cytometry 3. The benefit of treatment with VenObi+VenZan in terms of rate of patients with uMRD, L-MRD and H-MRD in the PB and BM at month 15, 21, 27, 33, 36 by: a. ASO-PCR b. Flow-cytometry 4. Rate of patients with uMRD according to the clinical and the biologic characteristics of CLL 5. Progression Free Survival (PFS) at 36 months 6. Overall Survival (OS) at 36 months 7. Survival outcomes (OS and PFS) estimates at 36 months according to the: a. levels of MRD (uMRD, L-MRD, H-MRD); b. response (CR, PR, stable disease); c. treatment (Ven-Obi+Ven or VenObi+VenZan); d. the clinical and the biologic characteristics of CLL (CD38, CD49d, IGHV, FISH profile, mutations of TP53, NOTCH1, BIRC3, SF3B1) 8. The benefit of treatment with VenObi+Ven or VenObi+VenZan on the improvement of Hb value, granulocyte, and platelet counts and immunoglobulin levels. 9. The toxicity profile of treatment in terms of AE/SAE.;Timepoint(s) of evaluation of this end point: During and at the end of the study | — |
Countries
Italy
Contacts
Public ContactCentro Dati
Fondazione GIMEMA Franco Mandelli Onlus
Outcome results
None listed