Phase II Study of High-Dose Rituximab in High-Risk Chronic Lymphocytic Leukemia Patients in Suboptimal Response After Induction Immunochemotherapy

Chronic Lymphocytic Leukemia Clinical Trial

— HYDRIC  

Official title:

Phase II Study of High-Dose Rituximab in High-Risk Chronic Lymphocytic Leukemia Patients in Suboptimal Response After Induction Immunochemotherapy

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01625741
• Other study ID #: HYDRIC
• Status: Terminated
• Phase: Phase 2
• First received: June 6, 2012
• Last updated: September 28, 2015
• Start date: July 2012
• Est. completion date: May 2015

Study information

• Verified date: September 2015
• Source: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health ProductsBelgium: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

This study explores the potential to improve the quality of response obtained after induction treatment in Chronic Lymphocytic Leukemia (CLL), by giving a short and intense consolidation schema using high-dose rituximab. Patients in suboptimal response (Minimal Residual Disease persistence) after induction will be selected, as well as those who have a Minimal Residual Disease (MRD) relapse after having achieved MRD negativity.

Description:

This study is reserved for patients with residual disease at the end of therapy at the level of Minimal Residual Disease (MRD-positive either in the peripheral blood at least 6 months after the last dose of rituximab-containing immunochemotherapy or in the bone marrow at least 3 months after the last dose of rituximab-containing immunochemotherapy). Patients who have achieved MRD eradication and who have MRD relapse (reappearance of residual leukemic cells using 7/8-color flow cytometry in peripheral blood or bone marrow) are also eligible for the study.

Rituximab will be given intravenously at a monthly dose of 2000 mg four months (in total 4 doses of 2000 mg each), starting within one month after informed consent signature.

The patients will be followed during the treatment period with rituximab. A final evaluation will be done 3 months after the last dose of rituximab.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

• B-cell Chronic Lymphocytic Leukemia defined by standard NCI criteria in first line or in relapse

• > 18 years-old

• Presence of Minimal Residual Disease (MRD positivity) by Flow Cytometry criteria in these two clinical situations :

1. Patients in Complete Remission (defined by standard criteria including Bone Marrow examination) after rituximab-containing immunochemotherapy (ICT), who show persisting MRD either in the Peripheral Blood at least 6 months after the last dose of rituximab-containing immunochemotherapy or in the Bone Marrow at least 3 months after the last dose of rituximab-containing ICT

2. Patients in continuous CR 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 anthracycline (ex: Fludarabine-Rituximab, Fluda-Cyclophsphamide-Rituximab, FCR-Mitoxantrone, R-bendamustine…)

2. At least 4 cycles

• Patients should have recovered from the toxicities of ICT

• POOR PROGNOSTIC FEATURES (before induction ICT) defined by at least one of the following markers: stage C Binet, 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 and/or presence of bulky lymph nodes prior to induction therapy, absence of profound lymph nodes at response evaluation should have been confirmed by CT scan

• CIRS =6

• Absence of significant geriatric syndromes and/or significant limitations in instrumental activities of daily living (IADL)

• 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

Exclusion Criteria:

• Less than CR defined by standard criteria response after ICT

• Ongoing active infections (bacterial, viral or fungal)

• 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

• Uncontrolled autoimmune hemolytic anemia or thrombocytopenia

• Transformation into an aggressive B-cell malignancy (eg. diffuse large B-cell lymphoma, Hodgkin lymphoma)

• Pregnancy, breast feeding, female patients with 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 (AST, ALT) > 3 xULN

• Conjugated bilirubin > 2 xULN

• Prior autologous stem cell transplantation less than 12 months

• Prior allogeneic stem cell transplantation

• Central Nervous System 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 > 4 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)

• Participation in any clinical study or having taken any investigational therapy which would interfere with the study drug for a disease other than CLL, within 28 days prior to initiating the maintenance therapy.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Rituximab
2000 mg, IV, monthly, for 4 months (= 4 doses)

Locations

Country	Name	City	State
Belgium	ZNA Middelheim	Antwerpen
Belgium	Clinique Sud Luxembourg	Arlon
Belgium	AZ Sint-Jan	Brugge
Belgium	Clinique Saint Jean	Brussels
Belgium	Cliniques universitaires Saint Luc	Brussels
Belgium	ULB Erasme	Brussels
Belgium	Grand Hôpital de Charleroi	Charleroi
Belgium	UZ Gent	Gent
Belgium	Hôpital de Jolimont	Haine-Saint-Paul
Belgium	KUL Gasthuisberg	Leuven
Belgium	CHU ULg Sart Tilman	Liège
Belgium	CHR Clinique Saint Joseph	Mons
Belgium	Clinique Saint Pierre	Ottignies
Belgium	Heilig-Hartziekenhuis	Roeselaere
Belgium	Clinique universitaire de Mont Godinne	Yvoir

Sponsors (1)

Lead Sponsor	Collaborator
Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	rate of conversion into Minimal Residual Disease negativity	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 immunochemotherapy (ICT), or MRD relapse after ICT.	Month 7 (= 3 months after the last dose of rituximab)	No
Secondary	toxicity of the consolidation treatment by rituximab		from first administration of rituximab until end of follow-up period (= 12 months after the last rituximab administration)	Yes
Secondary	Pharmacokinetic/Pharmacodynamic correlation	correlation between the level of MRD conversion at month 7 and pharmacokinetic dosage of rituximab performed after each rituximab perfusions, 1 month and 3 months after last rituximab.	month 7	No
Secondary	quality of life study	from selection visit until last follow-up visit planned 1 years after the last rituximab perfusion	during 17 months	No