Clinical Trials /

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

NCT02911142

Description:

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.

Related Conditions:
  • HHV8-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • Primary Effusion Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lenalidomide Combined With Modified DA-EPOCH and Rituximab (EPOCH-R2) in Primary Effusion Lymphoma or KSHV-associated Large Cell Lymphoma
  • Official Title: Phase I/II Study of Lenalidomide Combined With Modified DA-EPOCH and Rituximab (EPOCH-R(2)) In Primary Effusion Lymphoma or KSHV-Associated Large Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 160171
  • SECONDARY ID: 16-C-0171
  • NCT ID: NCT02911142

Conditions

  • Primary Effusion Lymphoma
  • B-Cell Lymphoma

Interventions

DrugSynonymsArms
Lenalidomide1
Rituximab1
Prednisone1
Etopside1
Doxorubicin1
Vincristine1
Cyclophosphamide1

Purpose

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
           antiangiogenic 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-naive patients with primary effusion lymphoma
      treated with lenalidomide in combination with, DA-EPOCH and rituximab (DA-EPOCHR^2).

      Eligibility

        -  Adult patients greater than or equal to 18 years with pathology confirmed primary
           effusion lymphoma, including extracavitary variants, 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
           DAEPOCH (EPOCH-R^2) in patients with PEL and KSHV-associated large cell lymphoma

        -  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.

        -  Patients with HIV will generally be prescribed cART.

        -  In phase I, with up to 3 dose levels, 6-18 patients will be accrued (3-6 patients per
           level).

        -  In the phase II portion of the study, 15 evaluable patients will be enrolled over 48-60
           months and 12 months follow-up after the last patient 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.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalLenalidomide, Rituximab, Prednisone, Etopiside, Doxorubicin, Vincristine and Cyclophosphamide
  • Lenalidomide
  • Rituximab
  • Prednisone
  • Etopside
  • Doxorubicin
  • Vincristine
  • Cyclophosphamide

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Primary effusion lymphoma (PEL), including extracavitary variant, and KSHVassociated
             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 patients <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 (4 weeks
             if the therapy was a monoclonal antibody)

          -  Phase I or Phase II patients who have prior dose-adjusted EPOCH for treatment for PEL
             or KSHV-associated large cell lymphoma

          -  Phase II patients who have received any prior curative-intent therapy for PEL or
             KSHV-associated large cell lymphoma. Patients 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 patients with Gilbert's
                  syndrome as defined by >80% unconjugated

               -  Total bilirubin greater than or equal to 7.5 with direct fraction > 0.7 if
                  patient 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. Patients 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:(Phase I) Maximum tolerated dose of DA-EPOCH_R2
Time Frame:One year
Safety Issue:
Description:Association of treatment regimen with one-year overall survival

Secondary Outcome Measures

Measure:response rates and progression-free survival
Time Frame:from start of treatment to time of progression of KSHVlymphomaor death, whichever occurs first
Safety Issue:
Description:Evaluate response rates and progression-free survival, and event-free survival for primary effusion lymphoma treated with DA-EPOCH-R2
Measure:lenalidomide PK
Time Frame:C1D1, C1D7, C6D1
Safety Issue:
Description:Evaluate pharmacokinetics of lenalidomide in blood, effusion and CSF
Measure:HIV latency reversal
Time Frame:C1D1, C1D2, C1D6, EOT, follow-up
Safety Issue:
Description: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
Measure:tenofovir and tenofovirdiphosphate PK
Time Frame:C1D1, C1D7, C6D1
Safety Issue:
Description:Evaluate the pharmacokinetics of tenofovir and tenofovir-diphosphate in plasma and PBMCs, respectively

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Treatment Naive
  • Immune Modulatory
  • Chemotherapy
  • AIDS-Related Lymphoma
  • PEL

Last Updated

January 10, 2020