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