AzTrials
AzTrials

Chronic Lymphocytic LeukemiaPhase 2NCT00001586

Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): DNA Microarray Gene Expression Analysis

A Phase 2 study testing Rituximab, Fludarabine phosphate and Leukemic or stroma cells in people with Chronic Lymphocytic Leukemia, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Background: Combined therapy with rituximab and fludarabine is the treatment of choice for advanced stage chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). A new technology called deoxyribonucleic acid (DNA) microarray can be used to gain knowledge about the genetic basis of CLL/SLL. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphocytic Leukemia
What is being tested?
Rituximab, Fludarabine phosphate and Leukemic or stroma cells
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
105 participants
Where
1 siteUnited States
Study dates
Sep 1997to Nov 2011
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) will be made according to the World Health Organization (WHO) diagnostic classification. A lymphocyte count in excess of 5000/mcl is typically found in the leukemic variant but is not a pre-requisite for a diagnosis of SLL. Low, Intermediate or High-Risk Category of CLL/SLL, using the Modified Three-Stage Rai Staging System as follows:
  • Risk Category: Low Risk
  • Rai Stage: 0
  • Clinical Features: Elevated blood and marrow lymphocyte numbers only (L). (lymphocytes greater than 5000/microl in blood, and lymphocytes greater than 30 percent in marrow).
  • Risk Category: Intermediate Risk
  • Rai Stage: I
Show all 30Show fewer
  • Clinical Features: L + enlarged lymph nodes (LN)
  • Risk Category: Intermediate Risk
  • Rai Stage: II
  • Clinical Features: L + enlarged spleen or liver
  • Risk Category: High Risk
  • Rai Stage: III
  • Clinical Features: L + anemia (Hemoglobin less than 11 gm/dl)
  • Risk Category: High Risk
  • Rai Stage: IV
  • Clinical Features: L + thrombocytopenia (platelets less than 100,000/microl)
  • Patients in the modified Rai high risk group and select patients in the intermediate risk group will undergo treatment with Rituximab Fludarabine. To meet treatment criteria patients in the intermediate risk group should have evidence of active disease as demonstrated by at least one of the following criteria:
  • massive or progressive splenomegaly or lymphadenopathy;
  • presence of weight loss greater than 10% over the preceding 6 months;
  • constitutional symptoms of extreme fatigue, night sweats or recurrent fever of greater than 100 degrees F (documented fevers must be occurring without evidence of specific infection), and bone pain;
  • progressive lymphocytosis with an increase of greater than 50% over a 2 month period, or an anticipated doubling time of less than 6 months;
  • chronic infections either increased number or prolonged infections;
  • other high risk prognostic indicators such as excess elevation of beta-2-microglobulin, cluster differentiation 38 (CD38) expression and adverse cytogenetics may be used to better appraise the risk in each individual patient.
  • Patients with a diagnosis of CLL/SLL who do not meet the eligibility criteria for receiving Rituximab and Fludarabine (are not intermediate- or high-risk CLL/SLL), can enroll on the protocol for the purpose of donating cellular products. Such patients will not receive rituximab and fludarabine chemotherapy. At a later date, if it is documented that the patient does meet the criteria, then the patient may receive Rituximab and Fludarabine (after discussion with the Principal Investigator).
  • In a limited number of cases, patients with low-risk CLL/SLL may be initiated on Rituximab and Fludarabine treatment. For example, individuals who are candidates for bone marrow transplantation may be started on Rituximab Fludarabine as an induction regimen prior to transplantation. Additionally, some low-risk patients may be started on Rituximab and Fludarabine for psychological reasons (patient insistence on starting chemotherapy prior to disease progression). However, it must be stressed that low-risk CLL/SLL patients will be discouraged from initiating therapy except in these specific cases.
  • Age greater than or equal to 18 years of age.
  • Patients must have received no prior cytotoxic or monoclonal antibody therapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
  • Required initial laboratory tests: Blood urea nitrogen (BUN) and Creatinine values must be less than or equal to 1.5 times the normal values; alternatively, patients with creatinine clearance of greater than 50 ml per minute will also be eligible. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values must be less than or equal to 2.0 times normal values; patients with laboratory values greater than these levels may be enrolled on the protocol (after a specific approval from the Principal Investigator) if the values are due to a known, pre-existing liver disease. Bilirubin must be less than or equal to 2.0 mg/dl unless due to Gilbert's disease.
  • The patient must be competent to sign an informed consent, and sign the protocol consent form.

Who cannot join

  • Patients must not be pregnant or breastfeeding.
  • Patients with active autoimmune hemolytic anemia (AIHA)) grade III or higher (transfusion or steroids indicated) or immune thrombocytopenia (ITP) grade III or higher (platelets less than 50,000/microL) shall not be enrolled. Patients with a history of prior therapy to control either AIHA or ITP will be eligible, provided they do not require maintenance corticosteroids, and have not received monoclonal antibody therapy in the past 6 months. Patients developing AIHA or ITP on protocol may be managed as medically indicated on protocol but will generally not undergo fludarabine/rituximab treatment until resolution of hemolysis or thrombocytopenia to less than grade III.
  • Any patient with a medical condition that requires chronic use of corticosteroids shall not be enrolled.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Background:

  • Combined therapy with rituximab and fludarabine is the treatment of choice for advanced stage chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
  • A new technology called deoxyribonucleic acid (DNA) microarray can be used to gain knowledge about the genetic basis of CLL/SLL.
  • Genetic studies of CLL/SLL may improve our understanding of what happens in the disease, help determine which patients are most likely to respond to treatment with fludarabine and rituximab, and identify new treatments.
Read more

Objectives:

-To gain further knowledge about CLL/SLL and the role of rituximab and fludarabine in treating the disease.

Eligibility:

-Patients 18 years of age and older with low, intermediate or high-risk CLL/SLL.

Design:

  • Patients with low-risk CLL/SLL do not receive treatment, but are followed every 3 to 6 months and donate cells (through apheresis) or lymph nodes, or both, for research purposes.
  • Patients with intermediate or high-risk CLL/SLL receive standard treatment with rituximab and fludarabine for six 28-day treatment cycles. Rituximab is given on day 1 and fludarabine is given on days 1-5. (For the first cycle only, fludarabine treatment starts on day 2. This delay permits blood sampling on day 1 for the effect of rituximab on white blood cells.)
  • Laboratory tests and imaging studies are done periodically to monitor drug side effects and the response to treatment. Tests include bone marrow biopsy and aspiration, blood tests and x-rays, including positron emission tomography (PET) and computed tomography (CT) scans.
Read the detailed description

Background:

  • Due to their synergistic action and non-overlapping toxicity profiles, the combination of Rituximab and Fludarabine is the treatment of choice for advanced stage chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL).
  • As such, we have designed this protocol to better understand the genetic basis of CLL/SLL, to identify predictors of treatment response and to study the molecular effects of Rituximab Fludarabine on the leukemic cells.
  • A new technology utilizing complementary deoxyribonucleic acid (cDNA) microarrays now permits the simultaneous quantitation of the expression of thousands of genes; this methodology can evaluate defined cellular pathways, and also discover novel genes influencing cell biology.
  • In addition to improving our understanding of the pathogenesis of CLL/SLL, these molecular studies may identify new therapeutic targets in CLL/SLL, and may help to identify those CLL/SLL patients most likely to respond to the combination of Fludarabine and Rituximab.

Objectives:

  • Evaluate CLL/SLL patients during and following Rituximab Fludarabine chemotherapy for changes in lymphocyte gene expression using DNA microarray analysis.
  • Evaluate gene expression by DNA microarray analysis of leukemic cells in blood, bone marrow and lymph nodes.

Eligibility:

  • Low, Intermediate or High-Risk Category of CLL/SLL, using the Modified Three- Stage Rai Staging System
  • Age greater than or equal to 18 years.
  • Patients must have received no previous cytotoxic or monoclonal antibody therapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  • Patients must not be pregnant or breast-feeding.
  • Patients with active autoimmune hemolytic anemia (AIHA)) grade III or higher (transfusion or steroids indicated) or immune thrombocytopenia (ITP) grade III or higher (platelets less than 50,000/microL) shall not be enrolled.
  • Any patient with a medical condition that requires chronic use of corticosteroids shall not be enrolled.

Design:

  • Patients who do not require treatment will be followed every 3-6 months and will donate cellular products, bone marrow biopsies, bone marrow aspirates and/or lymph nodes for research purposes.
  • Patients who do require treatment will received the standard dose of the Rituximab monoclonal antibody and the standard dose of Fludarabine for a total of six cycles. In the first cycle, Rituximab will be given on day 1 with Fludarabine being given on days 2-6. This will allow for appropriate samplings of the effects of Rituximab on lymphocytes before during and at the end of the first 24 hours. In subsequent cycles 2-6, the Rituximab and day 1 Fludarabine can both be given on day 1.
Being tested
Rituximab, Fludarabine phosphate, Leukemic or stroma cells
Keywords
Genetics, Bone Marrow Transplantation, Immunosuppression, T Lymphocytes, Marrow Purging
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RituximabBiological

    Also called Rituximab 375 mg/m^2 by infusion on day 1, cycle 1. Repeated every 28 days.

    Rituxan

  • Fludarabine phosphateDrug

    Also called Fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.

    Fludara

  • Leukemic or stroma cellsOther

    Patients are eligible to donate cells for the purpose of analyzing leukemic cells. Cells can be donated by apheresis (e.g. 60-90 minute intravenous technique), lymph node biopsy (e.g. 3 biopsy/excision of lymph nodes)bone marrow biopsy (e.g. 2-4 separate bone marrow biopsies), and bone marrow aspiration (e.g. 3 to 5cc of marrow per aspirate).

Study groups in NCT00001586
Study groupRoleWhat they receive
Low-Intermediate Risk B-Cell PtsExperimentalPreviously untreated low or intermediate risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients (pts) not requiring chemotherapy. No rituximab fludarabine administered. Eligible to donate cells.
Receives: Other: Leukemic or stroma cells
Intermediate-high Risk B-Cell PtsExperimentalPreviously untreated intermediate or high risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients requiring chemotherapy. Rituximab 375 mg/m^2 by infusion on day 1, cycle 1 followed by fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.
Receives: Biological: Rituximab; Drug: Fludarabine phosphate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Gene Expression Post Chemo

    Changes in lymphocyte gene expression was measured by deoxyribonucleic acid (DNA) microarray analysis of circulating leukemic cells after completion of study treatment. A change in expression is defined as a >50% increase in circulating leukemic cells or a 30% decrease in circulating leukemic cells.

    Measured: 6 hours post treatment, and 24 hours post treatment

Secondary outcomes (1)

  1. Number of Participants With Adverse Events

    Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

    Measured: 13 years, 10.5 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Nov 1999 (estimated)
  2. Study startSep 1997
  3. Primary completionNov 2011
  4. Study completionNov 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
105 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00001586
Sponsor's protocol ID
970178
Other IDs
97-C-0178
Status last verified
Mar 2013
First submitted
3 Nov 1999
Last updated
15 May 2013
Data monitoring committee
No

Publications

  • Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34.

    PubMed 1139039

  • Keating MJ. Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol. 1990 Oct;17(5 Suppl 8):49-62.

    PubMed 1699283

  • Raife TJ, Demetroulis EM, Lentz SR. Regulation of thrombomodulin expression by all-trans retinoic acid and tumor necrosis factor-alpha: differential responses in keratinocytes and endothelial cells. Blood. 1996 Sep 15;88(6):2043-9.

    PubMed 8822923

  • Mo CC, Njuguna N, Beum PV, Lindorfer MA, Vire B, Lee E, Marti G, Wilson WH, Taylor RP, Wiestner A. Rapid clearance of rituximab may contribute to the continued high incidence of autoimmune hematologic complications of chemoimmunotherapy for chronic lymphocytic leukemia. Haematologica. 2013 Aug;98(8):1259-63. doi: 10.3324/haematol.2012.080929. Epub 2013 May 28.

    PubMed 23716541

  • Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, Gibellini F, Njuguna N, Lee E, Stennett L, Raghavachari N, Liu P, McCoy JP, Raffeld M, Stetler-Stevenson M, Yuan C, Sherry R, Arthur DC, Maric I, White T, Marti GE, Munson P, Wilson WH, Wiestner A. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011 Jan 13;117(2):563-74. doi: 10.1182/blood-2010-05-284984. Epub 2010 Oct 12.

    PubMed 20940416

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rituximab, Fludarabine phosphate and Leukemic or stroma cells in people with Chronic Lymphocytic Leukemia, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 May 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 May 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Gene Expression Post Chemo (time frame: 6 hours post treatment, and 24 hours post treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00001586, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 May 2013.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in