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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

2016-09-22 20:53:31 | BioPortfolio

Summary

PR(SqrRoot) CIS

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.

Main 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-EPOCHR2).

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

- Previously treated patients will be allowed in Phase I if they have not previously been treated with modified DA-EPOCH

- 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-R2) 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.

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.

Main 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-EPOCHR2).

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

- Previously treated patients will be allowed in Phase I if they have not previously been treated with modified DA-EPOCH

- 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-R2) 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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Primary Effusion Lymphoma

Intervention

Lenalidomide, Rituximab, Prednisone, Etopside, Doxorubicin, Vincristine, Cyclophosphamide on day 10 (for 6 cycles), each patient will get a 750 mg/m2 dose.

Location

National Institutes of Health Clinical Center
Bethesda
Maryland
United States
20892

Status

Not yet recruiting

Source

National Institutes of Health Clinical Center (CC)

Results (where available)

View Results

Links

Published on BioPortfolio: 2016-09-22T20:53:31-0400

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Medical and Biotech [MESH] Definitions

Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.

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