E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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 |
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E.1.1.1 | Medical condition in easily understood language |
Patient suffering B-cell CLL with presence of residual leukemic cells after standard treatment of their disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068919 |
E.1.2 | Term | B-cell chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
Toxicity of consolidation rituximab
Time to MRD relapse in responders
Progression-free survival (PFS), event-free survival (EFS), overall survival (OS)…
Analysis by disease subgroup
PK/PD correlation (correlation between MRD conversion and pharmacokinetics of rituximab)
Study of the recrudescence of CD20-negative clones (« shaving effect »)
Quality of Life study
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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). |
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E.5 End points |
E.5.1 | 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At final evaluation, 3 months after the 4th dose of rituximab high dose |
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E.5.2 | Secondary end point(s) |
Toxicity of consolidation rituximab
Time to MRD relapse in responders
Progression-free survival (PFS), event-free survival (EFS), overall survival (OS)…
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During rituximab treatment administration and follow-up visits |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |