Bortezomib and Romidepsin in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

April 19, 2018 updated by: Virginia Commonwealth University

Phase I Study of Bortezomib and Romidepsin in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Indolent B-Cell Lymphoma, Peripheral T-Cell Lymphoma or Cutaneous T-Cell Lymphoma

This phase I trial studies the side effects and best dose of giving bortezomib and romidepsin together in treating patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), indolent B-cell lymphoma, peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Bortezomib and romidepsin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin administered weekly x 3 every (q) 4wk in patients with CLL/SLL, indolent B-cell lymphoma, PTCL or cutaneous T-cell lymphoma (CTCL).

Secondary

  • Determine safety and tolerance and describe the toxicities of the combination.
  • Demonstrate adequate methods for the assessment of pharmacodynamic responses of CLL cells to the combination with respect to effects on NF-kappa B (nuclear RelA and processing of p52 as a marker of p100 processing), expression of the NF-kappa B-dependent proteins XIAP and Bcl-xL, and Bim, and document pharmacodynamic responses observed in the course of this study * Document the pharmacodynamic responses associated with this regimen in these patients.
  • Document the anticancer activity of this regimen in these patients.

OUTLINE: Patients receive bortezomib IV over 3-5 seconds and romidepsin IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples from patients with chronic lymphocytic leukemia are collected at baseline and after day 1 of course 1 of study treatment for pharmacodynamic and correlative laboratory studies.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Robert H. Lurie Comprehensive Cancer Center, Northwestern University
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland Greenebaum Cancer Center
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt-Ingram Cancer Center, Vanderbilt University
    • Virginia
      • Richmond, Virginia, United States, 23298
        • Virginia Commonwealth University/Massey Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following:

  • CLL or SLL, relapsed or refractory

  • Indolent B-cell lymphoma, relapsed or refractory:

    • Follicle center lymphoma, follicular or diffuse
    • Marginal zone B-cell lymphoma (splenic, nodal, extranodal [this includes mucosa associated lymphoid tissue (MALT)])
    • Lymphoplasmacytic lymphoma

  • PTCL, relapsed or refractory:

    • Anaplastic large cell lymphoma, anaplastic lymphoma kinase (ALK)-positive
    • Anaplastic large cell lymphoma, ALK-negative
    • Angioimmunoblastic T-cell lymphoma
    • Enteropathy-associated T-cell lymphoma
    • Extranodal natural killer (NK)/T-cell lymphoma, nasal type
    • Hepatosplenic T-cell lymphoma
    • PTCL, not otherwise specified (NOS)
    • Subcutaneous panniculitis-like T-cell lymphoma

  • CTCL:

    * CTCL with subtypes of mycosis fungoides Stage IB or higher, Sézary syndrome, or primary cutaneous anaplastic large cell lymphoma who have failed a previous systemic treatment, as per the following:

    • Stage IA plaque, IB, or IIA: At least 4 prior conventional and/or experimental regimens (topical or systemic, including psoralen-ultraviolet light [PUVA] and systemic corticosteroids)
    • Stage IIB, III, or IV: At least 1 prior systemic regimen (systemic corticosteroids alone or PUVA alone do not count as systemic regimens for this purpose) NOTE: Repeated use of the same regimen is considered 1 regimen

  • 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
  • No prior or concurrent CNS malignancy

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-1
  • ANC > 1,500/mm^3
  • Platelet count > 75,000/mm^3
  • Hemoglobin > 7.5 g/dL (transfusion allowed)
  • Serum creatinine ≤ 1.2 mg/dL or actual or calculated creatinine clearance > 60 mL/min
  • AST and ALT ≤ 2.5 times upper limit of normal (ULN)
  • Bilirubin ≤ ULN
  • Serum potassium ≥ 3.5 mEq/L (supplementation allowed)
  • Serum magnesium ≥ 1.7 mEq/L (supplementation allowed)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective non-hormonal contraception
  • Willing and able to comply with protocol requirements
  • No prior severe allergic reactions to bortezomib, boron, mannitol, or romidepsin
  • No progressing toxicity secondary to bortezomib
  • No grade 1 peripheral neuropathy with pain or ≥ grade 2 peripheral neuropathy by NCI-CTCAE criteria (v4.0) within the past 14 days

  • No condition related to ischemic heart disease, heart failure, or the risk of torsades de pointes or sudden cardiac death, including any of the following:

    • History of sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes, or resuscitated cardiac arrest unless currently addressed with an implantable cardiac defibrillator
    • Baseline heart rate > 140 beats per minute
    • Known congenital long QT syndrome
    • QTc interval > 480 milliseconds
    • Type II second-degree atrio-ventricular (AV) block, third-degree AV block, or ventricular rate < 50 beats per minute

    • Myocardial infarction within the past 6 months

      • Patients who have had a myocardial infarction 6-12 months ago are eligible provided they are asymptomatic and have a negative cardiac risk assessment (i.e., treadmill stress test, nuclear medicine stress test, or stress echocardiogram)

    • Angina upon ordinary physical activity

      • Angina only with strenuous, rapid, or prolonged exertion allowed

    • ECG with evidence of cardiac ischemia, as defined by the following:

      • ST depression of ≥ 2 mm, measured from isoelectric line to ST segment
      • T-wave inversion ≥ 4 mm, measured from isoelectric line to peak of T-wave
    • NYHA class II-IV congestive heart failure
    • Known left ventricular ejection fraction < 40% by MUGA scan or < 50% by echocardiogram or MRI
    • Known hypertrophic cardiomegaly or restrictive cardiomyopathy
  • No uncontrolled hypertension, defined as persistent blood pressure ≥ 160/95 mm Hg despite medical management
  • No clinically significant active infection, including known HIV infection or hepatitis B or C
  • No other malignancy within the past 3 years except completely resected basal cell carcinoma or squamous cell carcinoma of the skin, in situ malignancy, or curatively treated low-risk prostate cancer
  • No concurrent medical condition that, in the investigator's opinion, would compromise study treatment or assessment of toxicity

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • At least 3 weeks since prior chemotherapy, radiation therapy or investigational agents. If steroids for cancer control have been used, patients must be off theses agents for at least 1 week before starting treatment. (Maintenance therapy for non-malignant disease with prednisone or steroid equivalent dose less than 10 mg/day is permitted)
  • Prior allogeneic stem cell transplantation allowed provided all of the following conditions are met:
  • Greater than or equal to 6 months have elapsed since allogeneic transplant
  • No Graft vs. Host Disease (GVHD) is present
  • More than 4 weeks since prior bortezomib
  • No concurrent oral hormonal contraceptives
  • No concurrent potent or moderate CYP3A4 inhibitors
  • No concurrent anti-arrhythmic agents

  • No concurrent treatment with any drugs that are generally accepted to having a risk of causing torsades de pointes (class 1 drugs)

    • Class 2 or 3 drugs allowed at the discretion of the investigator
  • No other concurrent systemic therapy for the malignancy
  • Concurrent warfarin (coumadin) allowed

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: bortezomib + romidepsin
Bortezomib via a short intravenous infusion (3-5 seconds) followed by romidepsin via a 4 hour intravenous infusion weekly x 3 every 4 weeks. In order to identify appropriate doses, different subjects will be treated with different drug doses and observed for the effects, especially the side effects associated with higher doses.
Drug: Bortezomib
Starting dose: 1.3 mg/sq m
Other Names:
  • Velcade
  • PS-341
Drug: Romidepsin
Starting dose: 8 mg/sq m
Other Names:
  • depsipeptide
  • FK288

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum tolerated dose
Time Frame: 2 years
Dose at which no more than 1 dose-limiting toxicity is observed in as many as 6 patients
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacodynamic responses
Time Frame: 2 years
To explore candidate pharmacodynamic markers for use in subsequent phase II trials.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Virginia Commonwealth University

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Thomas C. Shea, MD, UNC Lineberger Comprehensive Cancer Center
  • Study Chair: Steven Grant, MD, Virginia Commonwealth University
  • Principal Investigator: Sho Ma, MD, PhD, Northwestern University & Robert H Lurie Comprehensive Cancer Center
  • Principal Investigator: Amy Kimball, MD, PhD, University of Maryland Greenebaum Cancer Center
  • Principal Investigator: Nishitha Reddy, MBBS, Vanderbilt-Ingram Cancer Center, Vanderbilt University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 26, 2010

Primary Completion (Actual)

July 17, 2014

Study Completion (Actual)

April 13, 2018

Study Registration Dates

First Submitted

August 20, 2009

First Submitted That Met QC Criteria

August 20, 2009

First Posted (Estimate)

August 21, 2009

Study Record Updates

Last Update Posted (Actual)

April 23, 2018

Last Update Submitted That Met QC Criteria

April 19, 2018

Last Verified

April 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MCC-12215 (Other Identifier: VCU Massey Cancer Center)
  • P30CA016059 (U.S. NIH Grant/Contract)
  • R21CA137823 (U.S. NIH Grant/Contract)
  • CDR0000652509 (Registry Identifier: PDQ)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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