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

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.

- 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.