Study of Pomalidomide Combined With Modified DA-EPOCH and Rituximab in KSHV-Associated Lymphomas

Background:

- Kaposi sarcoma herpesvirus (KSHV)-associated primary effusion lymphoma (PEL) and large
cell lymphoma arising from KSHV-MCD are aggressive B cell neoplasms 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

- Pomalidomide, an immune-modulatory derivative (IMiD) of thalidomide has in vitro

direct antitumor effect in KSHV-lymphomas as well as immune modulatory and antiangiogenic
effects that may be beneficial in treating both KSHV-NHL and in many patients, concurrent
KS.

- 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 KSHV-NHL, 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 HIVassociated
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:

-Determine the maximum tolerated dose and/or recommended phase II dose of pomalidomide in
combination with DA-EPOCH-R.

Phase II

-Evaluate overall survival in treatment-naive patients with primary effusion lymphoma
treated with pomalidomide in combination with, DA-EPOCH and rituximab (DAEPOCH- RP).

Eligibility:

-Adult patients greater than or equal to 18 years with pathology confirmed primary effusion
lymphoma,

including extracavitary variant OR large cell lymphoma arising in the setting of
KSHVassociated MCD.

- Lymphoma that is measurable or assessable

- Previously treated patients will be allowed if they have not been treated with modified
DA-EPOCH or pomalidomide for KSHV-associated lymphoma

- Any HIV status

- Hematologic and biochemical parameters within pre-specified limits at baseline

- 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 pomalidomide in combination with modified DA-EPOCH-R in
patients with PEL and diffuse large cell lymphoma arising in the setting of KSHVMCD.

- Phase I of the study will evaluate escalating doses of pomalidomide (3 mg, 4 mg, and 5
mg) in combination with modified DA-EPOCH-R to determine safe and tolerable phase II
pomalidomide dose for combination.

- Treatment in both Phase I and Phase II will have three parts. Patients will receive up
to 21 days of pomalidomide monotherapy (part A), followed by 6 cycles of pomalidomide
in combination with modified DA-EPOCH-R (part B), and then an optional up to 12 months
of pomalidomide (part C) for patients with concurrent KS, symptomatic KSHVMCD, or KSHV
inflammatory cytokine syndrome (KICS).

- Patients with HIV will generally be prescribed cART.

- In phase I, with 3 dose levels, 9-18 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:

2.1.1.1 KSHV-associated non-Hodgkin lymphoma, with pathology reviewed and confirmed at the
NIH. May include WHO recognized tumors

:

2.1.1.1.1 Primary effusion lymphoma (PEL), including extracavitary variant

2.1.1.1.2 Large cell lymphoma arising in the setting of KSHV-associated MCD.

2.1.1.2 Measurable or assessable lymphoma

2.1.1.3 Any HIV status

2.1.1.4 Age 18 years or greater. Because no dosing or adverse event data are currently
available on the use of pomalidomide 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.

2.1.1.5 ECOG performance status 0-4.

2.1.1.6 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 24 hours before starting pomalidomide 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 pomalidomide. 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 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

2.1.1.7 All study participants must agree to be registered into the mandatory POMALYST
REMS program, and be willing and able to comply with the requirements of the POMALYST
REMS program.

2.1.1.8 Able to take aspirin 81mg orally daily or if intolerant of aspirin, able to take a
substitute thromboprophylaxis such as low molecular weight heparin.

2.1.1.9 Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

2.1.2.1 Use of other systemic anticancer treatments or agents within the past 2 weeks (4
weeks if the therapy was a monoclonal antibody)

2.1.2.2 Prior dose-adjusted EPOCH or pomalidomide for treatment of KSHV-associated
lymphoma

2.1.2.3 Parenchymal brain involvement with lymphoma

2.1.2.4 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

2.1.2.5 Inadequate renal function, defined as calculated or estimated creatinine clearance
< 60 mL/min unless lymphoma related

2.1.2.6 Inadequate hepatic function:

--2.1.2.6.1 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

2.1.2.7 ANC < 1000/mm3 and platelets < 75,000/mm3 unless lymphoma, KSHV-MCD, or KICS-
related.

2.1.2.8 CTCAEv4.0 Grade 3-4 neuropathy

2.1.2.9 Ejection fraction less than 40% by echocardiography

2.1.2.10 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.

2.1.2.11 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.

2.1.2.12 Breast feeding (if lactating, must agree not to breast feed while taking
pomalidomide). Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with Pomalidomide, breastfeeding
should be discontinued if the mother is treated with Pomalidomide.

2.1.2.13 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.

2.1.2.14 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

2.1.2.15 Pregnant women are excluded from this study because pomalidomide 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