Clinical trial NCT00703664: Bortezomib and Vorinostat in Treating Patients With Recurrent Mantle Cell Lymphoma or Recurrent and/or Refractory Diffuse Large B-Cell Lymphoma
Official title: Phase II Trial of Bortezomib and Vorinostat in Mantle Cell and Diffuse Large B-Cell Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Recurrent Mantle Cell Lymphoma
Recurrent Non-Hodgkin Lymphoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-06-23
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial studies how well bortezomib and vorinostat work in treating patients with recurrent mantle cell lymphoma or recurrent and/or refractory diffuse large B-cell lymphoma. Bortezomib and vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Up to 9 years
Secondary outcomes:
measure: Best Response
timeFrame: Up to 9 years
measure: Progression-free Survival (PFS)
timeFrame: Up to 9 years
measure: Duration of Partial Response
timeFrame: Up to 9 years
measure: Duration of Stable Disease
timeFrame: Up to 9 years
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center-Weiler Hospital
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
Study officials:
affiliation: Massey Cancer Center
name: Beata Holkova
role: PRINCIPAL_INVESTIGATOR
References: