Front-line VenObi Combination Followed by Ven or VenZan Combination in Patients With Residual Disease: a MRD Tailored Treatment for Young Patients With High-risk CLL

NCT05478512 | Active Not Recruiting Phase 2

• 1 other identifier: CLL2222
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 8

Brief Summary

Multicentric phase 2 study for previously untreated high-risk CLL patients. Patients will receive 6 courses of the Venetoclax + Obinutuzumab combination.

• Patients with stable disease or a response (CR/PR) with uMRD in the PB and BM at cycle 9 will continue treatment with Venetoclax single agent until cycle 13 and then stop treatment.
• Patients with stable disease or a response (CR/PR) with evidence of residual disease in the PB and/or BM at cycle 9 will continue treatment with Venetoclax and Zanubrutinib combination until cycle 21. then, Patients with uMRD in the PB and BM at cycle 21 will stop treatment whereas patients with residual disease in the PB and/or BM at cycle 21 will discontinue Venetoclax and continue Zanubrutinib until disease progression.

Conditions

High Risk CLL; Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (2)

• Front-line VenObi efficacy in terms of MRD negativity

  Evaluation of front-line treatment (VenObi) efficacy in terms of percentage of patients who achieve Undetectable Minimal Residual Disease at the end of combination therapy

  at month 9

• VenZan efficacy in terms of MRD negativity

  Evaluation of treatment (VenZan) efficacy in terms of percentage of patients who achieve Undetectable Minimal Residual Disease in patients with residual disease at the end of combination therapy with VenObi

  at month 21

Study Arms (1)

VenObi+Ven or VenObi+VenZan

EXPERIMENTAL

Patients will receive VenObi combination followed by Venetoclax single agent or Venetoclax+zanubrutinib, according to MRD.

Drug: VenObi+Ven or VenObi+VenZan

Interventions

VenObi+Ven or VenObi+VenZan DRUG

Patients will receive obinutuzumab 1000mg IV (cycle 1: day 1,8,15; Cycle2-6: day1) + venetoclax 400mg/d (preceded by a ramp-up phase) until cycle 9, day 28. At cycle9: * if uMRD = Venetoclax 400 mg/d orally until cycle 13. * if residual disease in the BM or PB = Venetoclax 400 mg/d + Zanubrutinib 160 mg orally twice daily until cycle 21. then, at cycle 21: * if uMRD = stop treatment * if residual disease in the BM or PB = zanubrutinib 160 mg orally twice daily until disease progression

VenObi+Ven or VenObi+VenZan

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients older than 18 years and 65 years or less.
• Diagnosis of CLL meeting the iwCLL 2018 criteria.
• Total CIRS \<6, creatinine clearance \>30 ml/min \[Cockcroft-Gault\]) and ECOG performance status of 0-1.
• No prior treatment.
• Patients with unmutated IGHV, and, or TP53 mutation assessed by an ERIC certified laboratory, and, or deletion 17p assessed by FISH analysis.
• Active disease meeting at least 1 of the iwCLL 2018 criteria for treatment requirement.
• 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)
• 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
• QT-interval corrected according to Fridericia"s formula (QTcF) ≤450 milliseconds (ms).
• For females of childbearing potential, a negative serum pregnancy test within 7 days of study treatment.

You may not qualify if:

• 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.
• Known active histological transformation from CLL to an aggressive lymphoma (i.e., Richter's transformation or pro-lymphocytic leukemia);
• known central nervous system involvement.
• 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
• \. 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:

Sponsors & Collaborators

• Gruppo Italiano Malattie EMatologiche dell'Adulto: lead

Study Sites (8)

Ematologia AOU Careggi

Florence, Italy

Location

Ematologia IRST D.Amadori

Meldola, Italy

Location

Ematologia AO di Perugia

Perugia, Italy

Location

Ematologia Ospedale S.M. delle Croci

Ravenna, Italy

Location

Ematologia Ospedale Infermi

Rimini, Italy

Location

Ematologia Policlinico Gemelli

Roma, Italy

Location

Ematologia Policlinico Umberto I

Roma, Italy

Location

Ematologia AOUS - Policlinico S. M. alle Scotte

Siena, Italy

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 26, 2022
• First Posted: July 28, 2022
• Study Start: July 21, 2023
• Primary Completion: May 1, 2026
• Study Completion (Estimated): July 1, 2027
• Last Updated: March 17, 2026

Record last verified: 2026-03

Locations

IT (8)