Lenalidomide Combined With Modified DA-EPOCH and Rituximab (EPOCH-R2) in Primary Effusion Lymphoma or KSHV-associated Large Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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 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-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-MCD and KSHV-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 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-na(SqrRoot) ve 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 OS curve would demonstrate a 1-year OS consistent with 45% or better and ruling out 20% or worse.

Official Title
-----------------
Phase I/II Study of Lenalidomide Combined With Modified DA-EPOCH and Rituximab (EPOCH-R2) in Primary Effusion Lymphoma or KSHV-Associated Large Cell Lymphoma

Conditions
-----------------
Primary Effusion Lymphoma, B-Cell Neoplasm

Intervention / Treatment
-----------------
* Drug: Lenalidomide
* Drug: Rituximab
* Drug: Prednisone
* Drug: Etopside
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Any KSHV-positive aggressive B cell lymphomas, such as primary effusion lymphoma (PEL), and KSHV-associated large cell lymphoma that is pathologically confirmed by the NCI Laboratory of Pathology Measurable or assessable lymphoma. Any HIV status Age 18 years or greater. Because no dosing or adverse event data are currently available on the use of lenalidomide in combination with EPOCH-R in participants <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials. ECOG performance status 0-4. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 14 days prior to and again within 1 day before starting lenalidomide 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. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control All study participants must agree to be registered into the mandatory REVLIMID REMS program, and be willing and able to comply with the requirements of the REVLIMID REMS program. Able to take aspirin 81mg orally daily or if intolerant of aspirin, able to take a substitute thromboprophylaxis such as low molecular weight heparin. Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Use of other systemic anticancer treatments or agents within the past 2 weeks. The use of rituximab for the treatment of KSHV-associated MCD or KICS or the use of steroids are allowed within 2 weeks prior to start of treatment. Phase I or Phase II participants who have received prior dose-adjusted EPOCH for treatment for PEL or KSHV-associated large cell lymphoma Phase II participants who have received any prior curative-intent therapy for PEL or KSHV-associated large cell lymphoma. Participants who have received prior treatment as a bridge to curative-intent therapy will be considered per PI discretion. Parenchymal brain involvement with lymphoma History of malignant tumors other than KS or KSHV-associated MCD, unless: In complete remission for greater than or equal to 1 year from the time response was first documented or Completely resected basal cell carcinoma or In situ squamous cell carcinoma of the cervix or anus Inadequate renal function, defined as calculated or estimated creatinine clearance < 60 mL/min unless lymphoma, KSHV-MCD, or KICS- related for calculation of creatinine clearance) Inadequate hepatic function Bilirubin (total) > 1.5 times the upper limit of normal; AST and/or ALT > 3 times the upper limit of normal; EXCEPTIONS: Total bilirubin greater than or equal to 5 mg/dL in participants with Gilbert's syndrome as defined by >80% unconjugated Total bilirubin greater than or equal to 7.5 with direct fraction > 0.7 if participants is receiving a protease inhibitor at the time of initial evaluation Hepatic dysfunction attributed to lymphoma, KSHV-MCD, or KICS ANC <1000/mm3 and platelets < 75,000/mm3 unless lymphoma, KSHV-MCD, or KICS- related. CTCAEv5.0 Grade 3-4 neuropathy Ejection fraction less than 40% by echocardiography Known drug-related, inherited, or acquired procoagulant disorder including prothrombin gene mutation 20210, antithrombin III deficiency, protein C deficiency, protein S deficiency and antiphospholipid syndrome but not including heterozygosity for the Factor V Leiden mutation or the presence of a lupus anticoagulant in the absence of other criteria for the antiphospholipid syndrome. History of hypersensitivity reactions attributed to thalidomide, lenalidomide, or pomalidomide, including prior development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, lenalidomide, or pomalidomide. Breast feeding (if lactating, must agree not to breast feed while taking lenalidomide). Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lenalidomide, breastfeeding should be discontinued if the mother is treated with lenalidomide. Uncontrolled severe intercurrent illness including, but not limited to: bacterial, fungal, or life-threatening viral infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements. Participants with severe intercurrent illnesses attributed to lymphoma, KSHV-MCD, or KICS may be eligible per PI s or designee s discretion. Any condition, including laboratory abnormalities, which in the opinion of the Principal Investigator or Lead Associate Investigator, would prohibit administration of planned chemotherapeutic intervention, places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study Pregnant women are excluded from this study because lenalidomide is a Category X agent with the potential for teratogenic or abortifacient effects. These potential risks may also apply to other agents used in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Lenalidomide, Rituximab, Prednisone, Etopiside, Doxorubicin, Vincristine and Cyclophosphamide | Drug: Lenalidomide<br>* Lenalidomide taken orally, daily at assigned dose level on days 1 to 10, up to 25mg.<br>Drug: Rituximab<br>* During cycle 1, rituximab will be administered on day 4 prior to the start of EPOCH. During cycles 2 to 6, rituximab will be administered on day 1 of each cycle.<br>Drug: Prednisone<br>* During cycle 1, Prednisone 60 mg/m2 /day PO days 6 to 10. During cycles 2-6, Prednisone 60 mg/m2 /day PO days 1-5.<br>Drug: Etopside<br>* During cycle 1, Etoposide 50 mg/m2 /day continuous intravenous infusion days 6 to 9. During cycles 2-6, Etoposide 50 mg/m2/day continuous intravenous infusion days 1 to 4.<br>Drug: Doxorubicin<br>* During cycle 1, Doxorubicin 10 mg /m2/day continuous intravenous infusion days 6 to 9. During cycles 2-6, Doxorubicin continuous intravenous infusion days 1 to 4.<br>Drug: Vincristine<br>* During cycle 1, Vincristine 0.4 mg/m2 /day continuous intravenous infusion days 6 to 9. During cycles 2-6, Vincristine continuous intravenous infusion days 1 to 4.<br>Drug: Cyclophosphamide<br>* During cycle 1, Cyclophosphamide 750 mg/m2 day 10. During cycles 2-6, Cyclophosphamide 750 mg/m2 day 5.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase I) Maximum tolerated dose of DA-EPOCH_R2 | Association of treatment regimen with one-year overall survival | One year | 
| (Phase II) Overall survival in treatment-naive patients with primary effusion lymphoma treated with DA-EPOCH-R2 | Median amount of time subject survives post therapy | One year post end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response rates and progression-free survival | Evaluate response rates and progression-free survival, and event-free survival for primary effusion lymphoma treated with DA-EPOCH-R2 | from start of treatment to time of progression of KSHV-lymphoma or death, whichever occurs first | 
| lenalidomide PK | Evaluate pharmacokinetics of lenalidomide in blood, effusion and CSF | C1D1, C1D7, C6D1 | 
| HIV latency reversal | In HIV infected patients, evaluate the effect of lenalidomide alone and in combination with EPOCH-R on HIV latency reversal and cellular measures of HIV | C1D1, C1D2, C1D6, EOT, follow-up | 
| tenofovir and tenofovirdiphosphate PK | Evaluate the pharmacokinetics of tenofovir and tenofovir-diphosphate in plasma and PBMCs, respectively | C1D1, C1D7, C6D1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Treatment Naive, Immune Modulatory, Chemotherapy, AIDS-Related Lymphoma, PEL