Activity and Safety of Front-line Venetoclax and Rituximab in Young and Fit Patients With Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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Fludarabine, cyclophosphamide, and rituximab (FCR) is the gold treatment for fit and young patients with Chronic Lymphoid Leukemia (CLL). However, patients with a mutation known as IGVH unmutated and patients with a particular characteristic known as 'disrupted TP53' show an inferior outcome after FCR in terms of survival. Venetoclax as a single agent or combined with rituximab is an effective treatment for relapsed/refractory patients with IGVH unmutated CLL and/or del(17p) and is associated with a high rate of clinical responses.

Detailed Description
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Fludarabine, cyclophosphamide, and rituximab (FCR) is the gold treatment for fit and young (age ≤65 years) patients with CLL. However, IGVH unmutated patients and patients with disrupted TP53 show an inferior outcome after FCR in terms of PFS and OS. Venetoclax as a single agent or combined with rituximab is an effective treatment for relapsed/refractory patients with IGVH unmutated CLL and/or del(17p) and is associated with a high rate of clinical responses and MRD-negative responses. The achievement of a MRD negative response in CLL is the best treatment endpoint since it is associated with an improved PFS. In treatment-naive patients with unmutated IGVH and/or disrupted TP53 the venetoclax and rituximab combination could be a more effective regimen than FCR with a 15% increase in the CR rate.

Official Title
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Activity and Safety of Front-linevenetoclax and Rituximab Association (VeRiTAs) in Young and Fit Patients With Chronic Lymphocytic Leukemia (CLL) and Umutated IGVH and/or Disrupted TP53. A Phase 2 Multicenter Study

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients older than18 years and 65 years or less. Diagnosis of CLL meeting the IWCLL 2008 criteria. Total CIRS <6, creatinine clearance >30 ml/min [Cockcroft-Gault]) and ECOG performance status of 0-1. No prior treatment. Umutated IGVH and/or disrupted TP53. Active disease meeting at least 1 of the following the IWCLL 2008 criteria for treatment requirement. Adequate bone marrow function without transfusion <2 weeks of screening as follows: absolute neutrophil count (ANC) ≥1.0 x 109/L (growth factors administration is allowed); platelets ≥30 x 109/L. If thrombocytopenia due to BM involvement, platelets should be ≥ 30 x 109/L; hemoglobin value ≥8.0 g/dl. Adequate renal and hepatic function per local reference laboratory reference ranges Female patients of childbearing potential and non-sterile male patients must practice at least one of method of birth control with partner(s) beginning with initial treatment administration and continuing to 12 months after the last dose of Rituximab. Male patients must agree to refrain from sperm donation, from initial treatment administration until 12 months after the last dose of Rituximab. A signed informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study. Exclusion Criteria: Any significant concurrent, uncontrolled medical condition or organ system dysfunction and/or 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. Transformation of CLL to aggressive NHL (Richter's transformation or pro-lymphocytic leukemia). History of other malignancies Pregnant or lactating females. Inadequate renal function: CrCl <30 mL/min. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia. Subject is known to be positive for HIV. Evidence of other clinically significant uncontrolled condition(s) Prior or concomitant fruits and/or specific drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Multicenter, prospective, interventional, single arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Veritas<br>Step 1. All patients: venetoclax 5-weeks dose-titration phase with weekly increases in the dose of venetoclax. Step 2. All patients will receive 6 courses of the VR combination. Step 3. After 6 courses of VR combination: 3a. Patients with no response will be off treatment; 3b. Patients with clinical response (CR or PR) after 6 courses of VR combination will receive venetoclax as a single agent for 6 months. Then, patients will be observed clinically until disease progression or until month 36. | Drug: Venetoclax<br>* Venetoclax and rituximab association<br>Drug: Rituximab<br>* Venetoclax and rituximab association<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients achieving complete response (CR) |  | At 15 months from treatment start, which is the end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients achieving response | Overall response rate (ORR) | At 15 months from treatment start, which is the end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic myeloid leukemia, Umutated IGVH, Disrupted TP53