Bendamustine and Rituximab (BR) as Induction and Maintenance in Relapsed and Refractory Chronic Lymphocytic Leukemia

Study of Bendamustine and Rituximab as Induction Immunochemotherapy Followed by Maintenance Bendamustine and Rituximab in Relapsed and Refractory B-cell Chronic Lymphocytic Leukemia (CLL)

CLL is an incurable disease with conventional chemotherapy. In the absence of TP53 disruption, a chemoimmunotherapy (CIT) regimen is recommended as front-line and second-line treatment in those patients who attained a long progression-free survival (PFS) with the previous regimen. Bendamustine and rituximab (BR) is one of the most widely adopted CIT regimens, including second-line treatment. Unfortunately, durations of remission following BR combination therapy tend to be short in patients with heavily pre-treated disease or who have already received rituximab. The incorporation of a maintenance following induction chemotherapy to overcome the shorter remission durations in this population is a reasonable option.

Study Overview

• Status: Unknown
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: BR as Maintenance

• Study Type: Observational
• Enrollment (Actual): 112

Contacts and Locations

Study Locations

• Russian Federation
  • Ostrovitianov Str. 1
    • Moscow, Ostrovitianov Str. 1, Russian Federation, 117997
      • Semochkin Sergey

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Patients with relapsed or refractory CLL receiving treatment at the University Hematology Hospital and Ambulant clinic.

Description

Inclusion Criteria:

• Confirmed diagnosis of CD20-positive CLL that meets the iwCLL criteria (Hallek et al, 2008).
• Relapsed or refractory status of disease after at least one prior chemotherapy regimen.
• ECOG performance status of 0-2 at study entry
• Patients have not received prior therapy with bendamustine
• Prior therapy with rituximab is permitted, even in the setting of rituximab refractory disease.

For inclusion in the research part of maintenance therapy (phase B):

• At least a partial response (PR or better; Hallek et al, 2008) must be achieved after induction of BR (phase A)

Exclusion Criteria:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent document or complying with the protocol treatment.
• Pregnant or breast-feeding females.
• Known to be positive for human immunodeficiency virus (HIV) or infectious hepatitis (type B or C).
• Patients are not eligible if there is a prior history or current evidence of central nervous system or leptomeningeal involvement.
• Richter syndrome or chronic prolymphocytic leukemia.
• Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
• Concurrent use of other anti-cancer agents or treatments.
• Laboratory test results within these ranges: ANC ≤ 1000/μL, Platelet count ≤ 75,000/μL.
• Total bilirubin Total bilirubin ≥ 2X upper limit laboratory normal (ULN). Patients with non-clinically significant elevations of bilirubin due to Gilbert's disease are not required to meet these criteria.
• Serum transaminases AST (SGOT) and ALT (SGPT) ≥ 3 x ULN, and/or serum alkaline phosphatase ≥ 5 X ULN.
• New York Heart Association class 3-4 heart failure.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Experimental: 6 cycles BR -> 4 x BR; Induction plus BR as maintenance (N=56)	Drug: BR as Maintenance; Patients of the study group who have achieved at least a partial response after 6 cycles of BR induction will receive additionally 4 cycles of BR every 3 months as maintenance therapy.
Proper historical control: 6 cycles BR; Induction only (N=56)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	PFS is defined as the number of days from the date of first dose of any study drug (rituximab or bendamustine) to the date of disease progression or death, whichever occurs first. PFS will be compared with its proper historical control (BR as induction without subsequent maintenance).	42 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR is defined as the proportion of participants with an overall response (CR, CRi, nodular partial remission [nPR] plus partial remission [PR]) per the 2008 Modified IWCLL NCI-WG criteria.	Approximately 24 months after initial dose of study drug.
Overall Survival (OS)	OS is defined as number of days from the date of first dose of any study drug (rituximab or bendamustine) to the date of death.	60 months (6 months induction therapy, 12 months maintenance, 42 months long-term follow-up
Safety evaluations	To determine the safety and tolerability of induction chemotherapy and maintenance therapy separately for two groups as assessed by CTCAE v4.0:	Up to 30 months
Health Related Quality of Life (HRQoL)	To determinate the effect of maintenance therapy on HRQoL using the EORTC Core quality of life questionnaire (QOL-C30, version 3.0).	Up to 30 months

Collaborators and Investigators

• Sponsor: Pirogov Russian National Research Medical University
• Investigators: Principal Investigator: Sergey Semochkin, Professor, Pirogov Russian National Research Medical University

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2013
• Primary Completion (Actual): December 3, 2019
• Study Completion (Anticipated): December 3, 2020

Study Registration Dates

• First Submitted: January 15, 2019
• First Submitted That Met QC Criteria: February 18, 2019
• First Posted (Actual): February 20, 2019

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 14, 2020
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Rituximab; Maintenance; Chronic Lymphocytic Leukemia; Bendamustine Hydrochloride
• 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
• Other Study ID Numbers: RSMU-CLL-2013

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No