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

Primary Effusion Lymphoma Clinical Trial

Official title: Phase I/II Study of Pomalidomide Combined With Modified DA-EPOCH and Rituximab in KSHV-Associated Lymphomas (Primary Effusion Lymphoma and Large Cell Lymphoma Arising in KSHV-Associated Multicentric Castleman Disease)

Status Withdrawn

Clinical Trial Summary

Background:

• The chemotherapy combination DA-EPOCH-RP includes the drugs etoposide (E), prednisone (P), vincristine (O), cyclophosphamide (C), doxorubicin (H), rituximab (R), and pomalidomide (P). Researchers want to see if including pomalidomide will help people with two rare lymphomas.

Objectives:

• To study the safety and efficacy of the chemotherapy drugs DA-EPOCH-RP.

Eligibility:

• Adults at least 18 years old. They must have primary effusion lymphoma or large cell lymphoma arising from Kaposi sarcoma Herpesvirus-associated multicentric Castleman disease.

Design:

• Participants will be with screened with blood tests, scans, spinal tap, and bone marrow sample. They may have skin or lymph node samples taken and fluid removed from around some organs.

• Participants will have breathing and eye tests. A camera may take pictures inside their body.

• Participants will take pomalidomide alone by mouth for up to 21 days. Then they will get rituximab by intravenous (IV) catheter, which is a small tube that goes into a vein..

• Participants will have an IV inserted in an arm or chest vein to get the IV chemotherapy drugs, at the same time the will take pomalidomide by mouth for 5 days.

• They will get DA-EPOCH-RP in 21-day cycles. Most people will have 6 cycles.

• They will get 4 study drugs by IV for 5 days and 2 others by mouth for 5 days.

• They will get daily filgrastim injections in the skin until white blood counts are acceptable

• For 2 days of some cycles, methotrexate will be injected into the spinal fluid.

• After completing EPOCH-RP, some participants who have Kaposi sarcoma will be prescribed pomalidomide for 3-weeks, followed by a one week break, for up to 12 months.

• Participants will repeat the blood tests often. They will also have repeated medical history, physical exam, urine and stool tests, and pictures of any rashes associated with these lymphomas.

• Participants will have several follow-up visits over 4 years.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Giant Lymph Node Hyperplasia
• Large Cell Lymphoma Arising in KSHV-associated Multicentric Castleman Disease
• Lymphoma
• Lymphoma, Non-Hodgkin
• Primary Effusion Lymphoma

• NCT number: NCT02228512
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• Start date: August 15, 2014
• Completion date: May 5, 2015