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

Phase 2

Completed

Conditions: Recurrent Mantle Cell Lymphoma
Recurrent Non-Hodgkin Lymphoma

Interventions: Drug: Bortezomib
Other: Laboratory Biomarker Analysis
Drug: Vorinostat

Registration Number: NCT00703664

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 65

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (vorinostat, bortezomib)	Laboratory Biomarker Analysis	Participants receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Participants also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Vorinostat precedes bortezomib on days of concurrent administration. Courses repeat every 3 weeks in the absence of disease progression - or unacceptable toxicity. After completion of study therapy, participants are followed periodically. Treatment arm consists of 3 cohorts, all receiving the same treatment: A: Mantle Cell Lymphoma (MCL) - with no prior bortezomib. B: Mantle Cell Lymphoma (MCL) - with no prior bortezomib. C: Diffuse Large B-Cell Lymphoma (DLBCL) - with no prior bortezomib.
Treatment (vorinostat, bortezomib)	Bortezomib	Participants receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Participants also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Vorinostat precedes bortezomib on days of concurrent administration. Courses repeat every 3 weeks in the absence of disease progression - or unacceptable toxicity. After completion of study therapy, participants are followed periodically. Treatment arm consists of 3 cohorts, all receiving the same treatment: A: Mantle Cell Lymphoma (MCL) - with no prior bortezomib. B: Mantle Cell Lymphoma (MCL) - with no prior bortezomib. C: Diffuse Large B-Cell Lymphoma (DLBCL) - with no prior bortezomib.
Treatment (vorinostat, bortezomib)	Vorinostat	Participants receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Participants also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Vorinostat precedes bortezomib on days of concurrent administration. Courses repeat every 3 weeks in the absence of disease progression - or unacceptable toxicity. After completion of study therapy, participants are followed periodically. Treatment arm consists of 3 cohorts, all receiving the same treatment: A: Mantle Cell Lymphoma (MCL) - with no prior bortezomib. B: Mantle Cell Lymphoma (MCL) - with no prior bortezomib. C: Diffuse Large B-Cell Lymphoma (DLBCL) - with no prior bortezomib.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	Up to 9 years	ORR: Complete Response (CR) + Partial Response (PR) assessed according to the Revised Response Criteria for Malignant Lymphoma.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	Up to 9 years	Median progression-free survival in months per cohort.
Duration of Partial Response	Up to 9 years	Median duration of response per cohort.
Duration of Stable Disease	Up to 9 years	Median duration of stable disease per cohort.
Best Response	Up to 9 years	Number of participants per category: Partial Response (PR), Stable Disease (SD), Progressive Disease (PD). PR: Regression of measurable disease and no new sites. SD: Failure to attain Complete Response (CR), /PR or PD. Relapsed or Progressive Disease: Any new lesion or increase by ≥ 50% of previously involved sites from nadir.

Trial Locations

Locations (12): Emory University Hospital/Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
Rutgers Cancer Institute of New Jersey
🇺🇸
New Brunswick, New Jersey, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
Weill Medical College of Cornell University
🇺🇸
New York, New York, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Montefiore Medical Center-Weiler Hospital
🇺🇸
Bronx, New York, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States