Tolerance and Efficacy of Subcutanous Low Doses Rituximab for CLL Consolidation Treatment (LLCRlowdoz)

Phase II Study of Tolerance and Efficacy of Subcutanous Low Doses Rituximab Given as Consolidation Treatment to Chronic Lymphocytic Leukaemia (CLL) Patients Responding to Induction Therapy

Chronic Lymphocytic Leukemia (CLL) is still an incurable disease. However recent advances have established correlation between the quality of the response (in particular achievement of negativity of minimal residual disease (MRD) and progression free and overall survival. That is why MRD negative complete remission (CR) is the current goal in CLL treatment.

The association of Rituximab fludarabine cyclophosphamide leads to the best response rate with 52 to 72% CR in "medically" fit untreated CLL patients. MRD results in this setting are still preliminary and around 50%. However many other situations (unfit, elderly, relapse, haematological toxicity leading to early interruption of treatment…) are associated with much lower response rate that would be improved by consolidation treatment.

Monoclonal antibodies are the treatment of choice for consolidation because of sparing marrow and targeting CLL cells. Alemtuzumab has been used for this purpose and results confirm improvement of CR and MRD negative responses but alemtuzumab induced immunodeficiency lead to unacceptable infectious complications. Rituximab monotherapy induces low response rate at standard dose regimen. This is at least partially due to shaving of CD20, mechanism by which CD20 is lost from the leukemic cells but these cells are not cleared. Using low doses of rituximab reduced shaving and allowed CLL cells clearance by the mononuclear phagocytic system. Such low doses of rituximab can be administered subcutaneously.

The investigators then propose subcutaneous low dose rituximab in consolidation to CLL patients responding after induction but having not achieved MRD negative CR.

Study Overview

• Status: Unknown
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Rituximab

Detailed Description

Objective(s) of the clinical study

Main objective:

- To improve the minimal residual disease (MRD) negative complete response (CR) rate after consolidation using subcutaneous low dose of rituximab

Secondary objectives:

• Progression free survival, treatment free survival, overall survival,
• MRD follow-up,
• Safety
• Medico-economic study
• Quality of life study
• Immune functions study (ancillary study)

Main assessment criteria:

MRD negative CR rate, established by peripheral blood 4colour flow cytometry according to international consensus on CLL MRD study, at the end of the consolidation treatment.

Experimental plan:

Inclusion of patients after the evaluation of response to induction treatment according to NCI-ICLLWG criteria and MRD analysis (2 to 3 months after induction completion): patients having not achieved MRD negative CR.

Consolidation treatment by subcutaneous rituximab given at 20 mg/m²/d thrice weekly during 12 weeks.

Evaluation of the response 3 months after completion of the consolidation treatment.

Subjects number: 35 patients will be needed to accept the hypothesis of an augmentation of CR with negative MRD >=40%, excluding the hypothesis that this rate is < 20%. This ensure us an alpha risk at 5% with a 80% power, taking into account that non evaluable patients will be < 5%.

Brief description of the ancillary study:

Immune functions study before and after consolidation treatment by rituximab

• Study Type: Interventional
• Enrollment (Anticipated): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Marseille, France, 13009
    • Institut Paoli Calmettes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• CLL (Matutes 4 or 5) in CR after induction treatment with negative MRD or PR
• age>18
• performance status<=2
• signed informed consent

Exclusion Criteria:

• cytopenia
• other malignant affection
• HIV or HBV positive
• steroids treatment
• richter syndrome
• pregnant or breastfeeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rituximab; Consolidation treatment with sub cutaneaous low doses of Rituximab	Drug: Rituximab; Low doses of sub cutaneaous rituximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Residual disease	- minimal residual disease (MRD) negative complete response (CR) rate after consolidation using subcutaneous low dose of rituximab, from randomisation up to 3 month after the end of treatment	up to 3 month after the end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival	time between inclusion and death	From date of inclusion until date of death, assessed up to 10 years
Adverse events	Number and description of adverse events recorded according to the CTC-AE V4	up to 3 months
-Quality of life	-Quality of life study by QLQ-C30	up to 3 months after the end of treatment
Immune functions	NK, monocytes, CD8, and CD 20 expression on leucemic cells or B cells	up to 3 months after the end of treatment
- Progression free survival	Time between inclusion and progression	up to time of progression assessed up to 10 years
treatment free survival	time between end of treatment and restarting a new treatement	up to time of new treatment assessed up to 10 years

Collaborators and Investigators

• Sponsor: Institut Paoli-Calmettes
• Investigators: Principal Investigator: Thérèse AURRAN, MD, Institut Paoli-Calmettes

Publications and helpful links

Helpful Links

• Web site of the sponsor

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (ANTICIPATED): June 1, 2015
• Study Completion (ANTICIPATED): June 1, 2015

Study Registration Dates

• First Submitted: December 22, 2011
• First Submitted That Met QC Criteria: January 26, 2012
• First Posted (ESTIMATE): January 31, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): March 20, 2015
• Last Update Submitted That Met QC Criteria: March 19, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: MRD negative CR
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: LLCR lowdoz / IPC 2009-004