Lymphoma
Conditions
Keywords
stage I adult diffuse large cell lymphoma, contiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma
Brief summary
RATIONALE: Lenalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. It may also stimulate the immune system in different ways and stop cancer cells from growing. 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. It is not yet known whether lenalidomide is more effective with or without rituximab in treating diffuse large B-cell non-Hodgkin lymphoma. PURPOSE: This randomized phase II trial is studying lenalidomide to see how well it works when given with or without rituximab after standard chemotherapy in treating patients with diffuse large B-cell non-Hodgkin lymphoma.
Detailed description
OBJECTIVES: Primary * To assess the 1-year disease-free and relapse-free survival of patients with high- or high/intermediate-risk diffuse large B-cell non-Hodgkin lymphoma treated with maintenance therapy comprising lenalidomide with or without rituximab following standard chemotherapy. Secondary * To assess the 2-year disease-free survival of patients treated with these regimens. * To define the safety and toxicity profile of these regimens. * To perform antibody-dependent cellular cytotoxicity assays using peripheral blood mononuclear cell samples from these patients. * To assess the change in the number of natural killer cells by flow cytometric analysis. * To evaluate cytokines including, but not limited to, sIL-2R, IL-6, IL-15, IL-12, TNF-α, and IFN-γ in these patients. * To study the KIR genotype receptor and FCγR polymorphisms. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. * Arm II: Patients receive lenalidomide as in arm I and rituximab IV on day 8 of courses 1, 3, 5, 7, 9, and 11 in the absence of disease progression or unacceptable toxicity. Peripheral blood mononuclear cells are collected periodically for correlative studies. Samples are analyzed for change in the number of natural killer cells by flow cytometry; antibody-dependent cellular cytotoxicity by assay; cytokines; KIR genotype receptor; and FCγR polymorphisms. After completion of study therapy, patients are followed at 30 days and then every 3 months for 1 year.
Interventions
DRUGLenalidomide
Orally once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.
DRUGRituximab
Rituximab 375 mg/m2 intravenously (IV) starting on Day 8, Cycle 1 of lenalidomide. Rituximab will be repeated on Day 8 of odd numbered cycles (Cycles 1, 3, 5, 7, 9, and 11) for a total of 6 doses from randomization.
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Understand and voluntarily sign an Informed Consent form 2. Age \> 18 years at time of signing the Informed Consent Form 3. Able to adhere to the study visit schedule and other protocol requirements. 4. Patients with histological confirmation of diffuse large B cell lymphoma with at least one of the following characteristics: * High or intermediate IPI score (See Appendix 8.0 for IPI scoring criteria) * Patients who are still PET scan positive mid therapy with R-CHOP, but, have turned negative after completion of therapy. * Low risk International prognostic index ie., an IPI score of \<3 if age \>60 years or \<2 if age is less than or equal to 60 with c-myc positive by Fluorescent In situ Hybridization. 5. No other previous lymphoma therapy, hormonal therapy or surgery, except for standard therapy with R-CHOP with or without radiation and with or without prophylactic Methotrexate therapy. Patients must be enrolled within 4-12 weeks of completion of therapy. 6. At the time of study entry following standard therapy with R-CHOP±RT, patients should be in complete remission. 7. ECOG performance status of ≤ 2 at study entry 8. Laboratory test results within these ranges: * Absolute neutrophil count ≥ 1500/mm³ * Platelet count ≥100K /mm³ * Serum creatinine ≤ 2.0 mg/dL * Total bilirubin ≤ 1.5 mg/dL * AST (SGOT) and ALT (SGPT) ≤ 2 x ULN 9. Disease free of prior malignancies for ≥ 3 years with exception of currently treated basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. 10. All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the Revlimid REMS® program. •Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by the Revlimid REMS® program) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. 11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation, if patients are thought to be at an elevated risk of thrombosis.
Exclusion criteria
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the Informed Consent 2. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide). 3. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. 4. Use of any other experimental drug or therapy within 28 days of baseline. 5. Known hypersensitivity to thalidomide. 6. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. 7. Any prior use of lenalidomide. 8. Concurrent use of other anti-cancer agents or treatments. 9. Known positive for HIV or infectious hepatitis, type B or C. 10. A diagnosis of deep vein thromboses in the preceding 3 months of study enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival at 1 Year | From on-treatment date to disease recurrence, up to 1 year | Disease-free survival is the time from on-treatment to first relapse or death (whichever comes first). Those who are alive and without relapse are censored at the last date known alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival at 2 Years | From on-treatment date to disease recurrence, up to 2 years | Disease-free survival is the estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method where death is an event, with censoring for non-expired patients at last known date alive. |
| Number of Patients With Each Worst-Grade Toxicity | 30 days after completing treatment, for up to 13 months | Count of patients according to the worst-grade toxicity experienced by each, where worst-grade toxicity is per NCI common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death. Toxicities present at baseline and continuing without change in grade are excluded when considering worst-grade toxicity. |
Other
| Measure | Time frame |
|---|---|
| Investigate Potential Predictive Biomarkers of Clinical Response or Resistance to Lenalidomide | up to two years |
| Exploratory: Concordance Between IHC for GCB and Non-GCB Subtypes to the Gene Expression Profiles Associated With the Subtypes | up to two years |
Countries
United States
Participant flow
Recruitment details
This study began enrolling patients October 2008 and continued until November 2013 when its study accrual goal was met. Patients were recruited from two academic medical institutions, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center and the University of North Carolina Medical Center, Chapel Hill.
Pre-assignment details
Fifty-one patients signed consent to participate in this trial. Seven patients did not meet eligibility criteria, thus they did not receive treatment therapy and continue on study.
Participants by arm
| Arm | Count |
|---|---|
| Arm I: Lenalidomide Lenalidomide: Orally once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. | 22 |
| Arm II: Lenalidomide and Rituximab IV Patients receive lenalidomide as in arm I and rituximab IV on day 8 of courses 1, 3, 5, 7, 9, and 11 in the absence of disease progression or unacceptable toxicity.
Lenalidomide: Lenalidomide 20 mg daily, Days 1-21, followed by 7 days rest (28-day cycle). Cycles will be repeated every 28 days for a total of 12 cycles
Rituximab: Rituximab 375 mg/m2 intravenously (IV) starting on Day 8, Cycle 1 of lenalidomide. Rituximab will be repeated on Day 8 of odd numbered cycles (Cycles 1, 3, 5, 7, 9, and 11) for a total of 6 doses from randomization. | 22 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 |
| Overall Study | Death | 1 | 0 |
| Overall Study | disease progression | 3 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Arm I: Lenalidomide | Arm II: Lenalidomide and Rituximab IV | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 17 Participants | 32 Participants |
| Age, Continuous | 60 years | 59.0 years | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 18 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 19 Participants | 18 Participants | 37 Participants |
| Region of Enrollment United States | 22 participants | 22 participants | 44 participants |
| Sex: Female, Male Female | 12 Participants | 9 Participants | 21 Participants |
| Sex: Female, Male Male | 10 Participants | 13 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 22 | 22 / 22 |
| serious Total, serious adverse events | 8 / 22 | 1 / 22 |
Outcome results
Primary
Disease-free Survival at 1 Year
Disease-free survival is the time from on-treatment to first relapse or death (whichever comes first). Those who are alive and without relapse are censored at the last date known alive.
Time frame: From on-treatment date to disease recurrence, up to 1 year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I: Lenalidomide | Disease-free Survival at 1 Year | 0.818 years |
| Arm II: Lenalidomide and Rituximab IV | Disease-free Survival at 1 Year | 0.90 years |
Secondary
Disease-free Survival at 2 Years
Disease-free survival is the estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method where death is an event, with censoring for non-expired patients at last known date alive.
Time frame: From on-treatment date to disease recurrence, up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I: Lenalidomide | Disease-free Survival at 2 Years | 0.818 years |
| Arm II: Lenalidomide and Rituximab IV | Disease-free Survival at 2 Years | 0.757 years |
Secondary
Number of Patients With Each Worst-Grade Toxicity
Count of patients according to the worst-grade toxicity experienced by each, where worst-grade toxicity is per NCI common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death. Toxicities present at baseline and continuing without change in grade are excluded when considering worst-grade toxicity.
Time frame: 30 days after completing treatment, for up to 13 months
Population: Total number of patients reported with any toxicity
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I: Lenalidomide | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=2 | 6 participants |
| Arm I: Lenalidomide | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=4 | 5 participants |
| Arm I: Lenalidomide | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=3 | 6 participants |
| Arm I: Lenalidomide | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=5 | 0 participants |
| Arm I: Lenalidomide | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=1 | 2 participants |
| Arm II: Lenalidomide and Rituximab IV | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=5 | 0 participants |
| Arm II: Lenalidomide and Rituximab IV | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=1 | 0 participants |
| Arm II: Lenalidomide and Rituximab IV | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=2 | 8 participants |
| Arm II: Lenalidomide and Rituximab IV | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=3 | 8 participants |
| Arm II: Lenalidomide and Rituximab IV | Number of Patients With Each Worst-Grade Toxicity | Number of patients with WGT=4 | 5 participants |
Other Pre-specified
Exploratory: Concordance Between IHC for GCB and Non-GCB Subtypes to the Gene Expression Profiles Associated With the Subtypes
Time frame: up to two years
Other Pre-specified
Investigate Potential Predictive Biomarkers of Clinical Response or Resistance to Lenalidomide
Time frame: up to two years