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

Phase II Trial of Bortezomib and Vorinostat in Mantle Cell and Diffuse Large B-Cell Lymphomas

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Mantle Cell Lymphoma; Recurrent Non-Hodgkin Lymphoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Bortezomib; Drug: Vorinostat

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.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center - Moses Campus
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center-Weiler Hospital
    • New York, New York, United States, 10065
      • Weill Medical College of Cornell University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (vorinostat, 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Bortezomib; Bortezomib: 1.3 mg/m^2/d IV days 1, 4, 8, and 11.; Other Names: Velcade; MLN341; PS-341; LDP 341; [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid; PS341; Drug: Vorinostat; Vorinostat: 400 mg (total daily dose as a single dose) days 1-5 and 8-12.; Other Names: SAHA; Suberoylanilide Hydroxamic Acid; MSK-390; Zolinza; L-001079038; Suberanilohydroxamic Acid

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Response	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.	Up to 9 years
Progression-free Survival (PFS)	Median progression-free survival in months per cohort.	Up to 9 years
Duration of Partial Response	Median duration of response per cohort.	Up to 9 years
Duration of Stable Disease	Median duration of stable disease per cohort.	Up to 9 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Beata Holkova, Massey Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2008
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: June 20, 2008
• First Submitted That Met QC Criteria: June 20, 2008
• First Posted (Estimate): June 23, 2008

Study Record Updates

• Last Update Posted (Actual): August 7, 2018
• Last Update Submitted That Met QC Criteria: July 11, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Disease Attributes; Lymphoma, B-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Recurrence; Lymphoma, Mantle-Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Bortezomib; Vorinostat
• Other Study ID Numbers: NCI-2009-00275 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); N01CM62201 (U.S. NIH Grant/Contract); N01CM62204 (U.S. NIH Grant/Contract); N01CM00071 (U.S. NIH Grant/Contract); P30CA076292 (U.S. NIH Grant/Contract); N01CM00100 (U.S. NIH Grant/Contract); N01CM62208 (U.S. NIH Grant/Contract); CDR0000598308; MCC-15428 (Other Identifier: Moffitt Cancer Center); 8064 (Other Identifier: CTEP)