Study of efficacy of consolidation immunotherapy with rituximab at high dose in patients with chronic lymphocytic leukemia who do not achieve complete eradication of their disease after standard treatment

Phase 1

• Conditions: Patients with B-cell CLL who (1) fail to achieve eradication of minimal residual disease (MRD) after standard treatment (immunochemotherapy) of their disease, (2) who have recurrence of MRD at any time after standard immunochemotherapy; MedDRA version: 17.1Level: LLTClassification code 10068919Term: B-cell chronic lymphocytic leukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2011-005174-27-BE
• Lead Sponsor: Cliniques universitaires Saint Luc

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2012-02-21
• Study Completion: 2015-05-30
• Last Update Posted: 28 March 2022

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 6

Inclusion Criteria

- B-cell CLL defined by standard NCI criteria in first line or in relapse
- > 18 year-old
- Presence of MRD (MRD positivity) by FCM criteria (standardized 7/8-color FCM) in these two clinical situations :
1.Patients in CR (defined by standard criteria including BM examination) after rituximab-containing ICT, who show persisting MRD either in blood at least 6 months after the last dose of rituximab-containing chemoimmunotherapy or in BM at least 3 months after the last dose of rituximab-containing ICT
2.Patients in continuous CR but who show MRD relapse in PB or BM without clinical progression (as defined by NCI) at any time after ICT
- ICT should have comprised:
1. Rituximab combined with fludarabine, with or without an alkylating drug, with or without an anthracyclin (ex: FR, FCR, FCRM…)
2. At least 4 cycles
- Patients should have recovered from the toxicities of ICT
- POOR PROGNOSTIC FEATURES (before induction) defined by at least one of the following markers: stage C Binet before induction ICT, unmutated IgVH genes, 17p deletion, 11q deletion, Zap-70 positivity, high CD38, mutated IgVH genes if VH3-21 usage
- In addition, in patients with 11q deletion, absence of profound lymph nodes should have been excluded by CT scan
- CIRS < 6
- Absence of geriatric risk profile as determined by using the G8 geriatric screening tool if patient aged > 70 years
- Performance status (ECOG) < 2
- Neutrophils > 1000/microL, platelets > 100,000/microL
- Creatinine clearance > 50 ml/min (clearance can be reevaluated after adequate hydration of the patient)
- Patient’s written informed consent

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 15
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 15

Exclusion Criteria

- Less than CR response after ICT
- Ongoing active infections (bacterial, viral or fungal)
- Other uncontrolled malignant disease
- Known infection with HIV
- Subjects with any serological evidence of current or past hepatitis B or hepatitis C exposure are excluded unless the serological findings are clearly due to vaccination
- Concomitant treatment with steroids, or any immunosuppressive drug
- Ongoing auto-immune phenomena, clinically significant
- Transformation into an aggressive B-cell malignancy (eg. diffuse large B-cell lymphoma, Hodgkin lymphoma)
- Pregnancy, breast feeding, females of childbearing potential or male patients who are unwilling to use adequate contraception
- Intolerance to rituximab
- Concomitant severe disease (uncompensated cardiac insufficiency, severe respiratory insufficiency…)
- Severe hypogammaglobulinemia with recurrent infections, unless the patient is receiving substitutive IV immunoglobulins
- Transaminases > 3x ULN
- Conjugated bilirubin > 2x ULN
- Prior autologous stem cell transplantation less than 12 months
- Prior allogeneic stem cell transplantation
- CNS involvement
- Any coexisting medical or psychological condition that would preclude participation to the required study procedures
- Prior history of malignancies, other than CLL, unless subject has been free of the disease for >= 5 years. Exceptions include the following: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histologic finding prostate cancer (TNM stage of T1a or T1b).

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Evaluate the rate of conversion into MRD negativity 3 months after the administration of 4 monthly courses of high-dose (2000 mg) rituximab in high-risk CLL patients with suboptimal response after ICT, or MRD relapse after ICT;Secondary Objective: Toxicity of consolidation rituximab<br>Time to MRD relapse in responders<br>Progression-free survival (PFS), event-free survival (EFS), overall survival (OS)…<br>Analysis by disease subgroup<br>PK/PD correlation (correlation between MRD conversion and pharmacokinetics of rituximab)<br>Study of the recrudescence of CD20-negative clones (« shaving effect »)<br>Quality of Life study<br>;Primary end point(s): Rate of conversion of MRD-positivity into eradication of MRD (MRD-negative) using sensitive flow cytometry at 3 months after 4 courses of high-dose rituximab;Timepoint(s) of evaluation of this end point: At final evaluation, 3 months after the 4th dose of rituximab high dose

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Toxicity of consolidation rituximab<br>Time to MRD relapse in responders<br>Progression-free survival (PFS), event-free survival (EFS), overall survival (OS)…<br>;Timepoint(s) of evaluation of this end point: During rituximab treatment administration and follow-up visits