Bortezomib and Vorinostat in Treating Patients With Recurrent Mantle Cell Lymphoma or Recurrent and/or Refractory Diffuse Large B-Cell Lymphoma

This was a multicenter, non-randomized phase 2 trial using a Simon two-stage design with 3
cohorts.

PRIMARY OBJECTIVES:

I. Estimate the response rates of mantle cell and diffuse large B-cell lymphomas to
bortezomib and vorinostat combination therapy.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of the study regimen. II. Observe progression-free
survival and response durations. III. Observe the relationship between pretreatment lymphoma
cell nuclear v-rel reticuloendotheliosis viral oncogene homolog A (relA) and response.

OUTLINE:

Patients receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Patients also
receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Courses
repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Histologically confirmed mantle cell or diffuse large B-cell lymphoma; histological
material must be available for central pathological review; unstained histological
material -- slides or blocks -- must be available for correlative studies; archived
material from previous biopsies is acceptable, unless a patient's lymphoma has been
known to undergo histological transformation in the past, in which case a repeat
biopsy to confirm histology prior to enrollment is required; availability of material
must be confirmed at the time of registration, but material may be submitted
subsequent to registration and initiation of study treatment

- Measurable disease according to the Revised Response Criteria for Malignant Lymphoma;
this requires at least one lesion greater than 1.0 cm in diameter in both the long and
short axis as measured by spiral computed tomography (CT) scan or physical exam

- Prior allogeneic stem cell transplant is allowed provided that all of the following
conditions are met:

- >= 6 months have elapsed since allogeneic transplant

- No graft vs. host disease (GVHD) is present

- Not currently on immunosuppressive therapy

- Prior therapy:

- Mantle cell lymphoma:

- Previously treated or untreated

- No prior bortezomib

- Diffuse large B-cell lymphoma:

- At least one prior systemic therapy

- No prior bortezomib

- Note: Not intended for patients in first relapse who are candidates for
high dose therapy with stem cell support

- Life expectancy of greater than 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2

- Able to tolerate loperamide or other anti-diarrheal medications

- Absolute neutrophil count >= 1.5 x 10^9/L

- Platelets >= 75 x 10^9/L

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transferase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine within normal institutional limits or calculated creatinine clearance >= 60
mL/min according to the Cockcroft-Gault formula

- For patients with known human immunodeficiency virus (HIV) infection, a cluster of
differentiation (CD)4 count >= 0.5 x 10^9/L

- For patients whose last treatment included bendamustine or fludarabine, a CD4 count >=
0.4 x 10^9/L

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation and to report pregnancy or suspected pregnancy
while participating in the study

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Chemotherapy or large field radiotherapy within 3 weeks prior to entering the study

- Prior histone deacetylase inhibitor as cancer treatment

- Concurrent treatment with other investigational agents

- Plans for other concurrent cancer treatment; if steroids for cancer control have been
used, patients must be off these agents for >= 1 week before starting treatment;
exception: maintenance therapy for non-malignant disease with prednisone or steroid
equivalent dose < 10 mg/day is permitted

- History of brain metastasis including leptomeningeal metastasis

- Grade >= 2 neuropathy, regardless of cause

- Unable to take oral medications

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to bortezomib or vorinostat

- Not sufficiently recovered from previous treatment

- Medical or other condition (for example: uncontrolled infection; potentially life
threatening changes on electrocardiogram [EKG]) or concurrent treatment (for example,
marrow suppressive agents such as zidovudine) that represents an inappropriate risk to
the patient or likely would compromise achievement of the primary study objective;
patients should be closely monitored when given bortezomib in combination with the
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and inducers

- Pregnant women are excluded from this study; breastfeeding should be discontinued

- Active concurrent malignancy, except adequately treated non-melanoma skin cancer