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10/22/2009 02:32 PM Posted by: Dr. H. Alejandro Preti

Primary Objectives

  1. To determine the response rates of patients with relapsed and/or refractory non Hodgkin lymphoma treated with a combination of Vorinostat and Bortezomib.

Secondary Objectives

  1. To determine the progression free survival of these patients treated with this regimen.
  1. To determine the safety and tolerability profile of this regimen in these patients.
  1. To conduct exploratory analyses to correlate response rate and progression free survival with pre-treatment and post-treatment nuclear factor kappa B (NFkB), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), cyclin D1, histone acetylation, Epstein Barr virus (EBV) related proteins, and cancer testis antigens (CTA) expression.

Rationale:

The incidence of non-Hodgkin lymphoma (NHL) continues to rise independently of the AIDS epidemic. Despite improvements in mortality and primary treatments of this heterogeneous group of malignancies the majority of patients with indolent lymphomas and a substantial fraction of patients with aggressive lymphomas will have disease recurrence and succumb to their illness. Novel, more selective and less toxic, therapeutic strategies are warranted to improve cure rates and prolong survival in this patient population.

Amongst the multiple new pathways recently studied two have emerged as potentially important targets for new agents in lymphoma. These include the ubiquitin proteasome pathway and the biochemical reactions that control histone acetylation. The first two agents in each class to have been studied in lymphomas are: bortezomib and vorinostat. Bortezomib has been granted FDA approval for the treatment of mantle cell lymphoma and has established activity in a variety of B-cell lymphomas including follicular, marginal zone and diffuse large B-cell lymphoma. Vorinostat or SAHA (suberoylanilide hydroxamic acid) has been FDA approved for the treatment of refractory cutaneous T-cell lymphomas and has also shown activity in other lymphomas.

Synergistic activity between vorinostat and bortezomib has been observed in different lymphoma cell lines. Recently published data showed that mantle cell lymphoma cell lines responded dramatically to the combination of bortezomib and vorinostat decreasing the cyclin D1 to undetectable levels. There are multiple levels of potential interaction between vorinostat and bortezomib which could explain their observed synergistic activity including: NFkB inhibition, increased TRAIL activation, increased levels of cyclin D kinase inhibitors and increase expression of tumor suppressor genes such as p53, E2F, and Bax.

In the profoundly immune deficient, NHL is frequently caused by infection with the ubiquitous EBV. Whether mild, subclinical immune deficiency is related to the development of NHL is unknown. We will therefore attempt to better understand the anti-tumor immune response in this patient population before and after treatment with the combination of vorinostat and bortezomib.

Phase I trials of combination vorinostat and bortezomib in patients with solid tumors and multiple myeloma have established the recommended dose as vorinostat 400 mg daily days 1 through 14 and bortezomib 1.3 mg/m2 days 1, 4, 8, and 11 every 21 days. Based on these findings we propose to conduct a phase II trial of the combination vorinostat and bortezomib at the recommended dose-schedule in patients with recurrent and/or refractory lymphomas, indolent and aggressive, and B- or T-cell lymphoma.

Eligibility Criteria:

Inclusion Criteria: Patients must have:

1) Histologically confirmed non–Hodgkin Lymphoma (sections for central pathology review MUST be available) including small lymphocytic lymphoma, lymphoplasmacytic lymphoma, follicular center cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, diffuse large B cell lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, anaplastic large cell lymphoma, nasal NK/T cell lymphoma, mycosis fungoides/Sezary syndrome, angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphomas not otherwise specified.

2) Received 2 or more prior therapies, which may include hematopoietic cell transplant (HCT).

3) Received treatment with a nucleoside analog, or an alkylating agent, an anthracycline and/or in the case of B cell lymphomas, rituximab.

4) Resistant disease to 2 regimens or resistant disease to at least 1 regimen after first relapse.

5) Bi-dimensionally measurable disease documented within 30 days prior to enrollment. Bi-dimensionally measurable disease is defined as:

a) A lymph node or tumor mass that can be accurately measured in two dimensions by CT, MRI, medical photograph (skin or oral lesion), plain X-ray, PET scan or other conventional technique and a greatest diameter of 1 cm or greater; or palpable lesions with both diameters > 2 cm (lesion measured in 2 largest perpendicular dimensions in millimeters);

b) For the purposes of this protocol, disease should be located in an area of no prior radiation therapy or a clear progression in an area that was previously irradiated.

6) Adequate organ and marrow function obtained less than or equal to 14 days prior to enrollment as defined by a(n):

a) Absolute neutrophil count (ANC) greater than or equal to 1,000/microliter

b) Platelet count greater than or equal to 100,000/microliter, or greater than or equal to 75,000/microliter if the bone marrow is involved

c) Hemoglobin level greater than or equal to 9 g/dL

d) Total bilirubin less than or equal to 1.5 x institutional upper limit of normality (ULN). (If abnormal, direct bilirubin less than or equal to 1.5 x institutional ULN)

e) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) less than or equal to 2.5 x institutional ULN (less than or equal to 5 x institutional ULN if liver involvement with lymphoma)

f) Serum creatinine less than or equal to 1.5 x institutional ULN

7) Zubrod (ECOG) Performance Status of 0 or 1 (corresponds to Karnofsky Performance Status (KPS) greater than or equal to 70%).

8) Age greater than or equal to 18 years.

9) Life expectancy greater than or equal to 3 months as clinically determined by referring physician.

10) Female patient is either post menopausal, free from menses for > 2 years, surgically sterilized or willing to use 2 methods of contraception (i.e., a condom in conjunction with a diaphragm, or spermicidal jelly; or oral, injectable, or implanted birth control; or abstinence ) to prevent pregnancy throughout the study, starting with visit 1.

11) Female patients of childbearing potential must have a negative serum pregnancy test (beta-HCG) within 72 hours of enrollment and should not be nursing due to the potential for congenital abnormalities and of harm to nursing infants due to this treatment regimen.

12) Male patient agrees to use an adequate method of contraception (i.e., a condom if female partner uses a diaphragm, spermicidal jelly; or oral, injectable, or implanted birth control; or abstinence) for the duration of the study and for 12 weeks after the last dose.

13) Patient must be able to swallow capsules as per clinical evaluation by study MD.

14) Signed and dated institutional review board/ethics committee-approved informed consent before any protocol specific screening procedures are performed.

15) Both men and women of all races and ethnic groups are eligible for this trial.

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