Background: Primary effusion lymphoma (PEL) is a rare disease with no standard treatment. Researchers want to see if a drug called lenalidomide along with common chemotherapy drugs may be effective in treating PEL. Objective: To test a new treatment for PEL. Eligibility: People ages 18 and older with PEL. Design: Participants will be screened with blood tests, imaging studies, a physical exam, and other tests. Participants will have tests to evaluate their disease. These may include: Blood tests Scans Lumbar puncture. Fluid around the spinal cord will be removed with a needle. Bone marrow removed with a needle and studied Samples of skin or lymph nodes removed Fluid removed from around organs Lung and eye tests Tubes with cameras taking pictures of airways or digestive tract Participants will take lenalidomide pills for 10 days. They will keep a pill diary. Participants will have a catheter (small tube) placed in the large vein in the arm or chest. Participants will get DA-EPOCH-R as intravenous infusions by catheter over several days. This will be repeated in 21-day cycles. Most participants will have 6 cycles. Participants will get the drug filgrastim by injection under the skin. They will get the drug methotrexate injected into the spinal fluid. During the study, participants will have the following tests done at least once: Medical history Physical exam Blood, urine, and stool tests Lesions photographed and measured Lumbar puncture Participants will have follow-up visits for 5 years. They will repeat the screening tests plus have urine and stool tested. Participants may be contacted later by phone to see how they are doing.
Background * Kaposi sarcoma herpesvirus (KSHV)-associated primary effusion lymphoma (PEL) is an aggressive B cell neoplasm with clinicopathologic and molecular profiles distinct from other AIDS-related lymphomas. * There are no prospective studies on these rare lymphomas. Clinical experience is limited; however, reported prognosis is poor, with median survival estimated at less than 6 months using conventional cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like chemotherapy. * Novel treatment is urgently needed for KSHV-associated lymphomas, and the therapeutic approach must take into account concurrent KSHV-associated malignancies which are commonly seen in this patient population * Lenalidomide, an immune-modulatory derivative of thalidomide (IMiD drug) has in vitro direct antitumor effect in KSHV-lymphomas as well as immune modulatory and anti-angiogenic effects that may be beneficial in treating PEL. * Rituximab, an anti-cluster of differentiation 20 (CD20) monoclonal antibody, has recently been shown to be an active agent in the management of KSHV-MCD. Although PEL is a CD20-negative tumor, advances in the understanding the biology of KSHV-infection of B-cells, the pathobiology of IL-6 syndromes in KSHV-Multicentric Castleman disease (MCD) and KSHV-non-Hodgkin lymphoma (NHL), and clinical experience using rituximab in the treatment of KSHV-MCD, support use of rituximab in the treatment of PEL, especially in patients with concurrent KSHV-MCD. * Modified dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA)-EPOCH is an anthracycline-based regimen that allows for personalization of dose-intensity showing that inclusion of etoposide and infusional administration decreases tumor cell resistance. * The use of DA-EPOCH in combination with rituximab for the treatment of human immunodeficiency virus (HIV) associated diffuse large B-cell lymphoma or Burkitt lymphoma has been shown to be safe and effective. * Given the central role of controlling HIV viremia with combination antiretroviral therapy (cART) in the management of KSHV-associated malignancies, as well as the likely contribution of uncontrolled HIV viremia to PEL pathogenesis, cART will be employed as an important part of the treatment regimen. Objectives Phase I \- Evaluate safety and tolerability of lenalidomide in combination with DA-EPOCH-R and determine the maximum tolerated dose and/or recommended phase II dose of this regimen. Phase II \- Evaluate overall survival in treatment-naive participants with KSHV-positive aggressive B cell lymphomas treated with lenalidomide in combination with DA-EPOCH and rituximab (DA-EPOCH-R\^2). Eligibility * Adult participants \>= 18 years with pathology confirmed any KSHV-positive aggressive B cell lymphomas, such as primary effusion lymphoma, and KSHV-associated large cell lymphoma * Lymphoma that is measurable or assessable * Any HIV status * Hematologic and biochemical parameters within pre-specified limits at screening * Willing to use effective birth control, as defined in the full protocol * Neither pregnant nor breast feeding * Excluded if other serious co-morbid condition that would prohibit administration of planned chemotherapeutic intervention is present Design * This is a phase I/ II study of lenalidomide in combination rituximab and modified DA-EPOCH (EPOCH-R\^2) in participants with KSHV-positive aggressive B cell lymphomas. * Phase I of the study will evaluate lenalidomide 25 mg days 1-10 in combination with modified DA-EPOCH-R to determine safety and tolerability. Dose de-escalation doses of lenalidomide are 20 mg and 15 mg. * Participants with HIV will generally be prescribed cART. * In phase I, with up to 3 dose levels, 6-18 participants will be accrued (3-6 participants per level). * In the phase II portion of the study, 15 evaluable participants will be enrolled over 48-60 months and 12 months follow-up after the last participant has enrolled, a 1-tailed 0.10 alpha level test would have 80% power to determine if overall survival (OS) curve would demonstrate a 1-year OS consistent with 45% or better and ruling out 20% or worse.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
17
Lenalidomide taken orally, daily at assigned dose level on days 1 to 10, up to 25mg.
During cycle 1, rituximab will be administered on day 4 prior to the start of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH). During cycles 2 to 6, rituximab will be administered on day 1 of each cycle.
During cycle 1, Prednisone 60 mg/m\^2 /day by mouth (PO) days 6 to 10. During cycles 2-6, Prednisone 60 mg/m\^2 /day PO days 1-5.
During cycle 1, Etoposide 50 mg/m\^2 /day continuous intravenous infusion days 6 to 9. During cycles 2-6, Etoposide 50 mg/m\^2/day continuous intravenous infusion days 1 to 4.
During cycle 1, Doxorubicin 10 mg /m\^2/day continuous intravenous infusion days 6 to 9. During cycles 2-6, Doxorubicin continuous intravenous infusion days 1 to 4.
During cycle 1, Vincristine 0.4 mg/m\^2 /day continuous intravenous infusion days 6 to 9. During cycles 2-6, Vincristine continuous intravenous infusion days 1 to 4.
During cycle 1, Cyclophosphamide 750 mg/m\^2 day 10. During cycles 2-6, Cyclophosphamide 750 mg/m\^2 day 5.
Screening
Baseline
Screening
Baseline
Screening
Screening
Day 6
Baseline
Baseline
Screening
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
(Phase I) Maximum Tolerated Dose (MTD) of Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (DA-EPOCH-R2)
The MTD is the dose level at which no more than 1 of up to 6 participants experiences dose-limiting toxicity (DLT) during the first two cycles of DA-EPOCH-R2 treatment. Association of treatment regimen with one-year overall survival. DLT is defined as any grade 4 adverse event at least possibly related to lenalidomide and not probably or definitely related to human immunodeficiency virus (HIV) or a Kaposi sarcoma-associated herpesvirus KSHV-associated malignancy resulting in a dose delay in etoposide phosphate, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) treatment \>2 weeks due to failure to resolve to grade 3 or lower. Any grade 3 cardiac toxicity that is at least possibly related to lenalidomide and not probably or definitely related to HIV or a Kaposi sarcoma-associated herpesvirus (KSHV)-associated malignancy resulting in a dose delay in DA-EPOCH-R treatment \>2 weeks due to failure to resolve to grade 2 or lower.
Time frame: First 6 weeks of treatment (2 cycles of treatment)
(Phase II) Overall Survival in Treatment-naive Participants With Primary Effusion Lymphoma Treated With Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (DA-EPOCH-R2) Reported Along With a 90% Confidence Interval
Median amount of time subject survives post therapy
Time frame: End of follow up period (5 years)
(Phase II) Overall Survival in Treatment-naive Participants With Primary Effusion Lymphoma Treated With Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (DA-EPOCH-R2) Reported Along With a 95% Confidence Interval
Median amount of time subject survives post therapy.
Time frame: End of follow up period (5 years)
Response Rate for Primary Effusion Lymphoma Reported Using a 90% Confidence Interval
Response rate is defined as the percentage of participants who have either a complete response (CR) or partial response (PR) for primary effusion lymphoma treated with etoposide phosphate, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R2) measured by the International Working Group Response Criteria for Malignant Lymphomas. Complete response (CR) is complete disappearance of all detectable evidence of disease. Partial response (PR) is at least a ≥50% decrease in the sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses.
Time frame: Response rate was calculated at the end of treatment (18 weeks of treatment)
Response Rate for Primary Effusion Lymphoma Reported Using a 95% Confidence Interval
Response rate is defined as the percentage of participants who have either a Complete Response (CR) or Partial Response (PR) for primary effusion lymphoma treated with etoposide phosphate, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R2) measured by the International Working Group Response Criteria for Malignant Lymphomas. Complete response (CR) is complete disappearance of all detectable evidence of disease. Partial response (PR) is at least a ≥50% decrease in the sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses.
Time frame: Response rate was calculated at the end of treatment (after 18 weeks of treatment)
Progression-free Survival (PFS) for Primary Effusion Lymphoma Treated With Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (DA-EPOCH-R2) Using a 90% Confidence Interval
PFS is defined as the duration of time from start of treatment to time of progression of Kaposi sarcoma-associated herpesvirus (KSHV)-lymphoma or death, whichever occurs first, measured by the International Working Group Response Criteria for Malignant Lymphoma. Progressive disease is appearance of any new nodal lesion ≥1.6 cm in greatest transverse diameter (GTD) or ≥1.1 cm in short axis during or after the end of therapy, even if other lesions are decreasing in size. At least a 50% increase from the nadir in the sum of the product of the diameters (SPD) of any previously involved nodes, or in a single involved node, or in the size of other lesions (e.g., splenic or hepatic nodules).
Time frame: Over follow-up period, a median of 26 months
Progression-free Survival (PFS) for Primary Effusion Lymphoma Treated With Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (DA-EPOCH-R2) Using a 95% Confidence Interval
PFS is defined as the duration of time from start of treatment to time of progression of Kaposi sarcoma-associated herpesvirus (KSHV)-lymphoma or death, whichever occurs first, measured by the International Working Group Response Criteria for Malignant Lymphoma. Progressive disease is appearance of any new nodal lesion ≥1.6 cm in greatest transverse diameter (GTD) or ≥1.1 cm in short axis during or after the end of therapy, even if other lesions are decreasing in size. At least a 50% increase from the nadir in the sum of the product of the diameters (SPD) of any previously involved nodes, or in a single involved node, or in the size of other lesions (e.g., splenic or hepatic nodules).
Time frame: Over a follow-up period, a median of 26 months
Event-free Survival (EFS) for Primary Effusion Lymphoma Treated With Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (DA-EPOCH-R2) Reported Along With a 90% Confidence Interval
Event-Free Survival (EFS) is defined as the duration of time from start of treatment to time of progression of Kaposi sarcoma-associated herpesvirus (KSHV)-lymphoma. Progressive disease was measured by the International Working Group Response Criteria for Malignant Lymphoma. Progressive disease is the appearance of any new nodal lesion ≥1.6 cm in greatest transverse diameter (GTD) or ≥1.1 cm in short axis during or after the end of therapy, even if other lesions are decreasing in size. At least a 50% increase from the nadir in the sum of the product of the diameters (SPD) of any previously involved nodes, or in a single involved node, or in the size of other lesions (e.g., splenic or hepatic nodules).
Time frame: Over a follow-up period, a median of 26 months
Event-free Survival (EFS) for Primary Effusion Lymphoma Treated With Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, and Rituximab (DA-EPOCH-R2) Reported Along With a 95% Confidence Interval
Event-Free Survival (EFS) is defined as the duration of time from start of treatment to time of progression of Kaposi sarcoma-associated herpesvirus (KSHV)-lymphoma. Progressive disease was measured by the International Working Group Response Criteria for Malignant Lymphoma. Progressive disease is the appearance of any new nodal lesion ≥1.6 cm in greatest transverse diameter (GTD) or ≥1.1 cm in short axis during or after the end of therapy, even if other lesions are decreasing in size. At least a 50% increase from the nadir in the sum of the product of the diameters (SPD) of any previously involved nodes, or in a single involved node, or in the size of other lesions (e.g., splenic or hepatic nodules).
Time frame: Over a follow-up period, a median of 26 months
Response Assessment of Kaposi Sarcoma Using the Modified Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Criteria Reported Along With a 90% Confidence Interval
Response was assessed by the percentage of participants with either a partial or complete response. Response was assessed using the Modified Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Criteria. Complete Response is the absence of any detectable residual disease, including tumor associated edema, persisting for at least 4 weeks. The absence of any detectable residual disease, including tumor associated edema, persisting for at least 4 weeks. Partial Response is a 50% or greater decrease in the number and/or size of previously existing lesions lasting for at least 4 weeks or no new lesions occurring in previously uninvolved areas of the body.
Time frame: At end of treatment (after 18 weeks treatment)
Response Assessment of Kaposi Sarcoma Using the Modified Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Criteria Reported Along With a 95% Confidence Interval
Response was assessed by the percentage of participants with either a partial or complete response. Response was assessed using the Modified Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Criteria. Complete Response is the absence of any detectable residual disease, including tumor associated edema, persisting for at least 4 weeks. The absence of any detectable residual disease, including tumor associated edema, persisting for at least 4 weeks. Partial Response is a 50% or greater decrease in the number and/or size of previously existing lesions lasting for at least 4 weeks or no new lesions occurring in previously uninvolved areas of the body.
Time frame: At end of treatment (after 18 weeks of treatment)
Response Rate of Participants With Active Multicentric Castleman Disease (MCD) Assessed by the National Cancer Institute (NCI) MCD Response Criteria Reported Along With a 90% Confidence Interval
Response rate is calculated by the percentage of participants with either a partial or complete response. Complete Response (CR) is full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are indicator abnormalities) probably or definitely attributable to MCD, lasting at least 3 weeks. Partial Response (PR) is at least 50% of the abnormalities probably or definitely attributed to Kaposi sarcoma-associated herpesvirus (KSHV)-MCD must improve by the minimum amounts specified to attain PR (e.g., C-reactive protein reduction to ≤50% of baseline; and Hemoglobin increment 2g/dL not explained by transfusion).
Time frame: At end of treatment (after 18 weeks of treatment)
Response Rate of Participants With Active Multicentric Castleman Disease (MCD) Assessed by the National Cancer Institute (NCI) MCD Response Criteria Reported Along With a 95% Confidence Interval
Response rate is calculated by the percentage of participants with either a partial or complete response. Complete Response (CR) is full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are indicator abnormalities) probably or definitely attributable to MCD, lasting at least 3 weeks. Partial Response (PR) is at least 50% of the abnormalities probably or definitely attributed to Kaposi sarcoma-associated herpesvirus (KSHV)-MCD must improve by the minimum amounts specified to attain PR (e.g., C-reactive protein reduction to ≤50% of baseline; and Hemoglobin increment 2g/dL not explained by transfusion).
Time frame: At end of treatment (after 18 weeks of treatment)
Kaposi's Sarcoma-associated Herpesvirus (KSHV)-Associated Inflammatory Cytokine Syndrome (KICS) Reported Along With a 90% Confidence Interval
Complete Response (CR) is full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are indicator abnormalities) probably or definitely attributable to KICS, lasting at least 3 weeks. Partial Response (PR) is at least 50% of the abnormalities probably or definitely attributed to KICS must improve by the minimum amounts (e.g., C-reactive protein reduction to ≤50% of baseline; and Hemoglobin increment 2g/dL not explained by transfusion). Progressive disease (PD) is at least two indicator abnormalities must deteriorate by the minimum amounts specified below to constitute PD (e.g., C-reactive protein increase by ≥50% of baseline (or the upper limit of normal, whichever is greater); Hemoglobin decrement 2g/dL not otherwise explained; and Platelet decrement ≥25,000/mm\^3 not otherwise explained). Stable disease (SD) is no change in signs and symptoms of KICS that meet criteria for any of CR, PR or PD.
Time frame: At the end of treatment (after 18 weeks of treatment)
Kaposi's Sarcoma-associated Herpesvirus (KSHV)-Associated Inflammatory Cytokine Syndrome (KICS) Reported Along With a 95% Confidence Interval
Complete Response (CR) is full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are indicator abnormalities) probably or definitely attributable to KICS, lasting at least 3 weeks. Partial Response (PR) is at least 50% of the abnormalities probably or definitely attributed to KICS must improve by the minimum amounts (e.g., C-reactive protein reduction to ≤50% of baseline; and Hemoglobin increment 2g/dL not explained by transfusion). Progressive disease (PD) is at least two indicator abnormalities must deteriorate by the minimum amounts specified below to constitute PD (e.g., C-reactive protein increase by ≥50% of baseline (or the upper limit of normal, whichever is greater); Hemoglobin decrement 2g/dL not otherwise explained; and Platelet decrement ≥25,000/mm\^3 not otherwise explained). Stable disease (SD) is no change in signs and symptoms of KICS that meet criteria for any of CR, PR or PD.
Time frame: At the end of treatment (after 18 weeks of treatment)
Pharmacokinetics of Lenalidomide in Blood
Bioanalytical measurements will be conducted on an ultra-high-performance liquid chromatography (uHPLC) with tandem mass spectrometric detection to determine the concentration of lenalidomide in blood using an assay developed and validated by the National Institutes of Health (NIH) Clinical Pharmacology Program.
Time frame: Cycle 1 Day 1(C1D1), C1D7, C6D1 (one cycle = 21 days)
Pharmacokinetics of Lenalidomide Effusion
Bioanalytical measurements will be conducted on an ultra-high-performance liquid chromatography (uHPLC) with tandem mass spectrometric detection to determine the concentration of lenalidomide in effusions using an assay developed and validated by the National Institutes of Health (NIH) Clinical Pharmacology Program.
Time frame: Cycle 1 Day 1(C1D1), C1D7, C6D1 (one cycle = 21 days)
Pharmacokinetics of Lenalidomide in Cerebrospinal Fluid (CSF)
Bioanalytical measurements will be conducted on an ultra-high-performance liquid chromatography (uHPLC) with tandem mass spectrometric detection to determine the concentration of lenalidomide in CSF using an assay developed and validated by the National Institutes of Health (NIH) Clinical Pharmacology Program.
Time frame: Cycle 1 Day 1(C1D1), C1D7, C6D1 (one cycle = 21 days)
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