Clinical Trials (PDQ®)
|Phase II||Biomarker/Laboratory analysis, Treatment||Closed||18 and over||NCI||NCI-2009-00441|
NCIC CTG C10404, SWOG C10404, CAN-NCIC-CL3, CALGB-10404, CDR0000584205, ECOG 10404, U10CA180821, U10CA031946, CL3, NCT00602459
This randomized phase II trial studies how well fludarabine and rituximab with or without lenalidomide or cyclophosphamide works in treating patients with symptomatic chronic lymphocytic leukemia. 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. 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. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Giving fludarabine and rituximab together with lenalidomide or cyclophosphamide may kill more cancer cells.
Further Study Information
I. To determine the two-year progression-free survival (PFS) after remission induction with four different chemo-immunotherapy combinations for patients with untreated, symptomatic, lower-risk and high-risk chronic lymphocytic leukemia (CLL) to decide which of the four arms, if any, to take forward into a randomized phase III trial.
II. To determine the induction response to fludarabine phosphate and rituximab (FR) and fludarabine phosphate, cyclophosphamide, and rituximab (FCR) in each of these arms, along with the consolidation response to lenalidomide in patients with CLL.
III. To determine the toxicity from these four chemoimmunotherapy combinations and that of consolidation therapy with lenalidomide.
IV. To determine the induction response and toxicity of FCR in patients with deletion (del) (11q22.3) along with consolidation response, 2-year PFS and toxicity of lenalidomide in this specific genetic group.
V. To determine the effect of pretreatment biologic characteristics on clinical outcomes, such as attaining a complete response to induction therapy and progression-free survival.
VI. To collect relapse samples to determine the frequency of clonal evolution among patients with immunoglobulin heavy chain variable region (IgVH) mutated and unmutated disease and to study mechanisms of resistance to chemoimmunotherapy.
VII. To determine if flow cytometry-negative status immediately post-therapy and at 24 months after study entry is an effective surrogate marker for prolonged progression-free survival and overall survival.
OUTLINE: Patients are randomized to 1 of 3 treatment arms (Arms A, B, or C). Patients on Arm A or B who are found to be del (11q22.3) positive are assigned to Arm D beginning with course 2 of induction therapy.
ARM A (remission-induction [RI] therapy with fludarabine phosphate and rituximab): Patients receive rituximab intravenously (IV) over 1-4 hours on days 1, 3, and 5 of course 1 and on day 1 of all subsequent courses. Patients also receive fludarabine phosphate IV over 30 minutes or orally (PO) on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.
ARM B (RI therapy with fludarabine phosphate and rituximab followed by remission-consolidation [RC] therapy with lenalidomide): Patients undergo RI therapy as in Arm I. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Patients with a complete or partial response or stable disease proceed to RC therapy beginning approximately 4 months after completing the last dose of fludarabine phosphate in course 6, comprising lenalidomide PO once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
ARM C (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide): Patients receive rituximab IV over 4 hours on days 1 and 3 of course 1 and on day 1 of all subsequent courses. Patients then receive fludarabine phosphate IV piggyback over 30 minutes or PO followed by cyclophosphamide IV piggyback over 30 minutes on days 1-3. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.
ARM D (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide followed by RC therapy with lenalidomide): Patients receive the first course of RI therapy as in Arm A or B before being re-assigned to Arm D. Beginning in course 2, patients receive rituximab IV on day 1 and fludarabine phosphate IV piggyback over 30 minutes or PO and cyclophosphamide IV piggyback over 30 minutes on days 1-3. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Patients with a complete or partial response or stable disease proceed to RC therapy beginning approximately 4 months after completing the last dose of fludarabine phosphate in course 6, comprising lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed up every 3 months for 1 year and then every 6 months for up to 15 years.
- Specific diagnosis of B-cell CLL:
- An absolute lymphocytosis of > 5,000/μL
- Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes
- Bone marrow examination must include at least a unilateral aspirate and biopsy; the aspirate smear must show > 30% of all nucleated cells to be lymphoid or the bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL; overall cellularity must be normocellular or hypercellular
- Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (cluster of differentiation [CD]19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers; additionally, the B-cells must be monoclonal with regard to expression of either kappa or lambda and have surface immunoglobulin expression of low density; patients with bright surface immunoglobulin levels must have CD23 co-expression
- Patients must have symptomatic and active intermediate or high-risk categories of the modified three-stage Rai staging system:
- Not eligible: low risk, Rai stage 0, lymphocytes (L) in blood (> 5000/uL) and marrow (> 30%) only
- Intermediate risk, Rai stage I, L + enlarged lymph nodes (LN)
- Intermediate risk, Rai stage II, L + spleen and/or liver (LN + or -)
- High risk, Rai stage III, L + anemia (hemoglobin < 11 gm/dL)
- High risk, Rai stage IV, L + thrombocytopenia (platelets < 100,000/uL)
- Patients in the intermediate-risk group must have evidence of active disease as demonstrated by at least one of the following criteria:
- Massive or progressive splenomegaly, hepatomegaly and/or lymphadenopathy
- Presence of weight loss > 10% over the preceding 6 month period
- Grade 2 or 3 fatigue
- Fevers > 100.5°F or night sweats for greater than 2 weeks without evidence of infection
- Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months
- No prior therapy for CLL, including no corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL
- No medical condition requiring chronic use of oral corticosteroids
- Performance status 0 - 2
- Patients with human immunodeficiency virus (HIV) infection may be eligible provided they meet the following criteria: no evidence of infection with hepatitis B or C; CD4+ cell count > 350/mm^3; no evidence of resistant strains of HIV; if not on anti-HIV therapy, an HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL; if on HIV therapy, HIV viral load < 50 copies HIV RNA/mL; and no history of acquired immune deficiency syndrome (AIDS)-defining condition; patients receiving concurrent zidovudine or stavudine may not be enrolled
- Non-pregnant and non-nursing
- In females of child-bearing potential randomized to Arm B or assigned to Arm D, a negative urine or serum pregnancy test with a sensitivity of at least 25 mIU/mL will be required: 1) 10-14 days prior to beginning lenalidomide consolidation therapy; and 2) within 24 hours prior to the first dose of lenalidomide consolidation therapy; in addition, females of childbearing potential in Arm B and Arm D with regular menses must have a pregnancy test performed weekly during the first 28 days of treatment, and then every 28 days while taking lenalidomide (including breaks in lenalidomide), at discontinuation of lenalidomide, and then 28 days following discontinuation of lenalidomide; if menses are irregular, a pregnancy test must be performed weekly during the first 28 days of treatment, and then every 14 days while taking lenalidomide, at discontinuation of lenalidomide, and at 14 and 28 days after discontinuation of lenalidomide; additionally, females of childbearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO reliable methods of birth control - one highly effective method (intrauterine device [IUD], hormonal [birth control pills, injections, or implants], tubal ligation, or partner's vasectomy), and one additional effective method (latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least 4 weeks before she begins lenalidomide therapy, while participating in the study, and for at least 4 weeks after completing lenalidomide therapy; "females of childbearing potential" is defined as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy, or who has had menses at any time in the preceding 24 consecutive months (not been naturally postmenopausal for at least 24 consecutive months)
- Male patients randomized to Arm B or reassigned to Arm D must agree not to father a child and to use a latex condom during any sexual contact with females of childbearing potential while taking lenalidomide and for at least 4 weeks following completion of lenalidomide therapy, even if the patient have undergone a successful vasectomy
- All patients randomized to Arm B or reassigned to Arm D must be counseled by a trained counselor every 28 days during consolidation therapy about pregnancy precautions and risks of fetal exposure
- Creatinine =< 1.5 x upper limit of normal
Trial Lead Organizations/Sponsors
National Cancer InstituteSouthwest Oncology Group
Eastern Cooperative Oncology Group
NCIC-Clinical Trials Group
|John Byrd||Principal Investigator|
|Southeast Cancer Center|
|Alan Philip Lyss||Ph: 800-392-0936|
|Goldschmidt Cancer Center|
|Alan Philip Lyss||Ph: 800-392-0936|
|Missouri Baptist Cancer Center|
|Alan Philip Lyss||Ph: 800-392-0936|
|Schiffler Cancer Center at Wheeling Hospital|
|Manish Monga||Ph: 304-293-2745|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00602459
ClinicalTrials.gov processed this data on October 22, 2014
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