Combination of Vorinostat and Bortezomib in Relapsed or Refractory T-Cell Non-Hodgkin's Lymphoma
Condition: Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell
Intervention: Vorinostat; Bortezomib
Intervention description: Dose of 200 mg by mouth twice daily on days 1-14 of each 21-day study.; Dose of 1.3 mg/m^2 by vein on days 1, 4, 8, and 11 of a 21 day cycle.
Intervention MeSH terms: Bortezomib; Vorinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Relapsed T-Cell Non-Hodgkin's Lymphoma; Refractory T-Cell Non-Hodgkin's Lymphoma; NHL; T-cell NHL; vorinostat; SAHA; Suberoylanilide Hydroxamic Acid; MSK-390; Zolinza; Bortezomib; Velcade; LDP-341; MLN341; PS-341; Peripheral T-cell lymphoma; CD 30 + anaplastic large cell lymphoma; Angioimmunoblastic T-cell lymphoma; Angiocentric/nasal type T/NK-cell lymphoma; Intestinal T-cell lymphoma; Hepatosplenic gamma delta T-cell lymphoma; Subcutaneous panniculitic T-cell lymphoma; Transformed Mycosis fungoides

Summary:

      Primary Objectives:

        1. To evaluate the response rate for patients with T-cell Non-Hodgkin's Lymphoma
           (NHL)receiving the combination of vorinostat and bortezomib

        2. To evaluate the safety and tolerability of the combination of vorinostat and bortezomib
           in patients with relapsed or refractory T-cell NHL.

      Secondary Objectives:

        1. To assess overall survival and time to treatment failure in patients with T-cell NHL
           treated with the combination of vorinostat and bortezomib.

        2. Correlative studies will be done to assess the role of vorinostat mediated apoptosis
           along with bortezomib synergy. Changes in marker expression from baseline to post
           treatment will be correlated with patient clinical response.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have an established diagnosis of relapsed or refractory T-cell NHL
             Eligible histologies include; Peripheral T-cell lymphoma (unspecified), CD 30 +
             anaplastic large cell lymphoma ( ALK-1 positive and ALK-1 negative),
             angioimmunoblastic T-cell lymphoma, angiocentric/nasal type T/NK-cell lymphoma,
             intestinal T-cell lymphoma, hepatosplenic gamma delta T-cell lymphoma, subcutaneous
             panniculitic T-cell lymphoma, transformed Mycosis fungoides; All patients must have
             had at last one prior system regimen (radiation therapy does not qualify as systemic
             treatment).

          2. Patients who are eligible for blood and marrow transplant can receive this treatment
             to maximal reduction of tumor bulk: A minimum of two cycles of therapy will be given
             before crossing over to transplant.

          3. Patients must have at least one clear-cut bi-dimensionally measurable site by physical
             exam and/or computed tomography: Baseline measurements of measurable sites and
             evaluation of evaluable disease must be obtained within four weeks prior to
             registration of this study.

          4. Patient may have had prior radiation therapy for localized disease: Therapy must be
             completed at last four weeks before the enrollment in the study.

          5. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
             to 2.

          6. Patients must be age 18 years old and above.

          7. Patients are required to have adequate bone marrow reserve as indicated: Absolute
             neutrophil count (ANC) >/= 1000/mm^3; Platelets >/= 80,000/mm^3; Hemoglobin >/= 8g/dL;
             If there is bone marrow involvement by lymphoma then there is no minimum level of
             counts required; These values must be obtained within two weeks before protocol entry.

          8. Patients must have adequate liver function as indicated by:Bilirubin </= 1.5 times the
             upper limit of normal (ULN); Alanine transaminase (ALT) </= 2 times the (ULN) or
             aspartate transaminase (AST) </= 2 times the ULN; These values must be obtained within
             two weeks before protocol entry.

          9. Patients are required to have adequate renal function as indicated by a serum
             creatinine </= 2.5 mg/dL; This value must be obtained within two weeks before protocol
             entry.

         10. Male patients must agree to use an accepted and effective method of contraception for
             the duration of the study.

         11. Female patients must be willing to use two adequate barrier methods of contraception
             to prevent pregnancy or agree to abstain from heterosexual activity throughout the
             study or be post menopausal (free from menses > two years or surgically sterilized).

         12. Female patients of childbearing potential must have a negative serum pregnancy test
             (Beta hCG) within 72 hours of receiving the first dose of vorinostat.

         13. Patients must have the ability able to give informed consent.

        Exclusion Criteria:

          1. Patients with: T-cell lymphoma with skin involvement only are excluded if they have no
             evidence of systemic disease; T-cell prolymphocytic leukemia (T-PLL); T-cell large
             granular lymphocytic leukemia; Primary cutaneous CD30+ disorders: anaplastic large
             cell lymphoma and lymphomatoid papulosis

          2. Patients with active Hepatitis B and/or Hepatitis C infection.

          3. Patients with known HIV infection are excluded: These patients are excluded secondary
             to potential to target activated T-cells, in a population of patients already at risk
             for T-cell depletion, would be a contraindication to therapy.

          4. Patients with active infections requiring specific anti-infective therapy are not
             eligible until all signs of infections are resolved.

          5. Patients with left ventricular ejection fraction (LVEF) < 45%.

          6. Patients with pre-existing cardiovascular disease requiring ongoing treatment. This
             includes: Congestive heart failure; Severe CAD; Cardiomyopathy; Uncontrolled cardiac
             arrhythmia; Unstable angina pectoris; Recent MI.

          7. Patients with prior exposure to either vorinostat (including other HDAC inhibitors
             except valproic acid) or bortezomib: Patients who have received valproic acid (VPA)
             for the treatment of seizures may be enrolled on this study, but must not have
             received VPA within 30 days of study enrollment.

          8. Patients who are pregnant or breast-feeding: Effects of this treatment on the fetus
             and young children are unknown at this time.

          9. Patients who have had an invasive solid tumor malignancy in the past five years except
             non-melanoma skin cancers or cervical carcinoma in situ or ductal/lobular carcinoma in
             situ of the breast who is currently without evidence of disease.

         10. Patients undergoing anti-neoplastic chemotherapy, radiation, hormonal (excluding
             contraceptives) or immunotherapy, or investigational medications within the past four
             weeks. Receipt of systemic corticosteroids within 7 days of study treatment unless
             patient has been taking a continuous dose of no more than 10 mg/day of prednisone for
             at least 1 month.

         11. Patients with deep vein thrombosis within three months.

         12. Patients with lymphoma involvement of the CNS.

         13. Patients who have undergone prior allogenic transplantation: Prior autologous
             transplantation is accepted.

         14. Patient with concurrent use of complementary or alternative medicines that would
             confound the interpretation of toxicities and anti-tumor activity of vorinostat and/or
             bortezomib.

         15. Patient with a history of allergic reaction attributable to compounds containing boron
             or mannitol.

         16. Patients with psychiatric illness and/or social situations that would limit compliance
             with the study medication and requirements.

         17. Patients with grade 2 or more neuropathy.