Rituximab, Fludarabine, Cyclophosphamide, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Relapsed B-Cell Non-Hodgkin's Lymphoma

August 27, 2012 updated by: Technical University of Munich

Safety and Efficacy of Sequential Treatment With a Combination of Rituximab, Fludarabine and Cyclophosphamide Followed by Zevalin (Rituximab and Y-Ibritumomab Tiuxetan) - A Phase I/II Study for Treatment of Patients With Relapsed Indolent and Transformed CD20-Positive B-Cell Non-Hodgkin's-Lymphoma Ineligible for High-Dose Chemo(Radio)Therapy Supported by Autologous Peripheral Blood Stem-Cells

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving rituximab and chemotherapy together with yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of yttrium Y 90 ibritumomab tiuxetan when given together with rituximab, fludarabine, and cyclophosphamide and to see how well they work in treating patients with relapsed B-cell non-Hodgkin's lymphoma.

Study Overview

Status

Unknown

Conditions

Lymphoma

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

Determine the dose-limiting toxicity and maximum tolerated dose of rituximab and yttrium Y 90 (^90Y) ibritumomab tiuxetan when administered with rituximab as radioimmunotherapy after rituximab, fludarabine, and cyclophosphamide in patients with relapsed indolent, mantle cell, or transformed CD20-positive B-cell non-Hodgkin's lymphoma.

Secondary

Determine the overall survival in patients treated with this regimen.
Determine time to progression and event-free survival in patients treated with this regimen.
Determine partial and complete response rates in patients treated with this regimen.
Determine time to maximal response in patients treated with this regimen.
Determine response duration in patients treated with this regimen.
Determine the feasibility of additional antineoplastic treatment following disease relapse after treatment with rituximab and ^90Y ibritumomab tiuxetan in these patients.

OUTLINE: This is a prospective, nonrandomized, multicenter, phase I dose-escalation study of yttrium Y 90 (^90Y) ibritumomab tiuxetan followed by a phase II open-label study.

Phase I:
- Chemoimmunotherapy: Patients receive rituximab IV on day 1 and fludarabine IV over 30 minutes and cyclophosphamide IV over 60 minutes on days 1-3. Treatment repeats every 4 weeks for up to 3 courses in the absence of disease progression. Four weeks after the first day of the last chemoimmunotherapy course, patients receive 1 dose of rituximab IV alone. Patients with disease progression are removed from the study. Patients with stable disease proceed to radioimmunotherapy 8-12 weeks after the first day of the last chemoimmunotherapy course.
- Radioimmunotherapy: Patients receive rituximab IV and an imaging dose of indium In III ibritumomab tiuxetan IV over 10 minutes on day 1. Patients then undergo imaging. If dosimetry is acceptable, patients receive rituximab IV and ^90Y ibritumomab tiuxetan IV over 10 minutes on day 8.

Cohorts of 3-6 patients receive escalating doses of ^90Y ibritumomab tiuxetan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Phase II: Patients receive chemoimmunotherapy and radioimmunotherapy as in phase I, at the MTD determined in phase I.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 2 years.

PROJECTED ACCRUAL: A total of 12 patients will be accrued for this study.

Study Type

Interventional

Enrollment (Anticipated)

Phase

Phase 2
Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Germany
- - Augsburg, Germany, D-86156
    - Medizinische Klinik, Klinikum Augsburg
  - Erlangen, Germany, D-91054
    - Medizinische Klinik III - Universitaetsklinikum Erlangen
  - Goettingen, Germany, D-37075
    - Universitaetsklinikum Goettingen
  - Luebeck, Germany, D-23538
    - Universitaetsklinikum Schleswig-Holstein - Campus Luebeck
  - Magdeburg, Germany, D-39120
    - Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
  - Mainz, Germany, D-55101
    - Universitätsklinik Mainz
  - Munich, Germany, D-81675
    - Klinikum Rechts der Isar - Technische Universitaet Muenchen
  - Munich, Germany, D-81366
    - LMU-Klinikum Grosshadern
  - Regensburg, Germany, D-93042
    - Klinikum der Universitaet Regensburg
  - Tuebingen, Germany, D-72076
    - Universitaetsklinikum Tuebingen
  - Ulm, Germany, D-89081
    - Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
  - Wuerzburg, Germany, D-97080
    - Medizinische Klinik und Poliklinik II - Universitaetsklinikum Wuerzburg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

Histologically confirmed CD20-positive B-cell non-Hodgkin's lymphoma (NHL), including any of the following subtypes:
- Indolent NHL, including any of the following:
  - Follicular
  - Lymphoplasmacytoid
  - Marginal zone
- Mantle cell NHL
- Transformed B-cell NHL
In at least first relapse with an indication for systemic antineoplastic treatment, as defined by the following:
- Local or constitutional (B-) symptoms
- Hypersplenism due to splenic involvement
- Bulky disease (> 7.5 cm in diameter)
- Impending medical problems derived from rapid disease progression within the past 6 months, as defined by an observed or anticipated > 50% increase in the sum of the areas calculated from multiplying the greatest perpendicular diameters of each lesion
Measurable lesions of lymphoma infiltration
Medically ineligible for high-dose treatment followed by autologous stem cell support
Adequate bone marrow cellularity (> 15% of marrow area covered by hematopoiesis)
No CNS, leptomeningeal, spinal cord, or testes lymphoma involvement
No lymphoma lesion mandating emergency radiotherapy
No clinical, cytological, cytogenetic, or histopathologic indication of myelodysplastic syndrome
If there is bone marrow infiltration detected prior to chemoimmunotherapy, patient must undergo a repeat bone marrow biopsy prior to planned treatment with radioimmunotherapy to verify the level of bone marrow infiltration is < 25%

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
Life expectancy ≥ 3 months
Absolute neutrophil count > 1,500/mm³
Platelet count > 150,000/mm³
Hemoglobin > 9 g/dL
Creatinine < 1.5 times upper limit of normal (ULN)
Bilirubin < 2 times ULN
ALT and AST < 2 times ULN
Albumin > 2.5 g/dL
INR < 1.5
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for ≥ 12 months after completion of study treatment
No concurrent severe and/or uncontrolled medical disease that would preclude study compliance, including any of the following:
- Uncontrolled diabetes
- Congestive heart failure
- Chronic renal disease
- Active uncontrolled infection
No bleeding risks or disorders, including any of the following:
- CNS abnormalities suggesting an increased susceptibility for hemorrhage, including recent history of stroke as demonstrated by cranial contrast-enhanced CT scan
- Severe arrhythmia or uncontrolled hypertension
- Myocardial infarction within the past 6 months
- Diabetic retinopathy with history of symptomatic hemorrhage
- Known and potentially active gastrointestinal bleeding foci
- Concurrent anticoagulant medication that must be continued even with platelet count < 20,000/mm³ (e.g., following mitral valve replacement, anti-phospholipid syndrome, or recurrent venous thromboembolism)
- Other congenital or acquired hemorrhagic diatheses
No ongoing autoimmune hemolytic anemia
No known presence of anti-murine antibody reactivity
No known hypersensitivity to murine or chimeric antibodies or proteins
No known HIV infection
No psychiatric illness that would preclude study requirements
No other malignant disorder within the past 10 years except basal cell carcinoma of the skin or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Recovered from prior therapy
No more than 4 prior systemic anti-lymphoma regimens (including single-agent rituximab)
At least 2 months since prior systemic anti-lymphoma treatment (including single-agent rituximab)
No prior radioimmunotherapy
No prior autologous or allogeneic hematopoietic stem cell transplantation
No prior treatment with purine analogues that has not resulted in remission for > 1 year
No prior anti-CD20 radioimmunoconjugate therapy
More than 5 years since prior radiotherapy to extensive fields covering lymph node regions on both sides of the diaphragm or > 50% of the spinal column
More than 4 weeks since prior surgery
No concurrent oral anticoagulant therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Dose-limiting toxicity

Secondary Outcome Measures

Outcome Measure
Survival
Response

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Technical University of Munich

Investigators

Study Chair: Christian Peschel, MD, Technical University of Munich

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2005

Primary Completion (Actual)

May 1, 2008

Study Completion (Anticipated)

May 1, 2013

Study Registration Dates

First Submitted

November 9, 2006

First Submitted That Met QC Criteria

November 9, 2006

First Posted (Estimate)

November 10, 2006

Study Record Updates

Last Update Posted (Estimate)

August 28, 2012

Last Update Submitted That Met QC Criteria

August 27, 2012

Last Verified

August 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

CDR0000515982
KRDI-TUM-R-F-015-V-0030-I
EU-20633

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.