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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

Phase 1
18 Years
Open (Enrolling)
Leukemia, Lymphoma

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Trial Information

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



- 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).


- 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

Inclusion Criteria


* 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 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


- 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

- 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


- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose

Outcome Description:

Dose at which no more than 1 dose-limiting toxicity is observed in as many as 6 patients

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Beata Holkova, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Massey Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

April 2010

Completion Date:

December 2014

Related Keywords:

  • Leukemia
  • Lymphoma
  • refractory chronic lymphocytic leukemia
  • stage I chronic lymphocytic leukemia
  • stage II chronic lymphocytic leukemia
  • stage III chronic lymphocytic leukemia
  • stage IV chronic lymphocytic leukemia
  • recurrent small lymphocytic lymphoma
  • contiguous stage II small lymphocytic lymphoma
  • noncontiguous stage II small lymphocytic lymphoma
  • stage I small lymphocytic lymphoma
  • stage III small lymphocytic lymphoma
  • stage IV small lymphocytic lymphoma
  • adult nasal type extranodal NK/T-cell lymphoma
  • anaplastic large cell lymphoma
  • angioimmunoblastic T-cell lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • hepatosplenic T-cell lymphoma
  • nodal marginal zone B-cell lymphoma
  • peripheral T-cell lymphoma
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, B-Cell
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, T-Cell, Peripheral



Robert H. Lurie Comprehensive Cancer Center, Northwestern UniversityChicago, Illinois  60611
University of North CarolinaChapel Hill, North Carolina  27599
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201
Virginia Commonwealth University/Massey Cancer CenterRichmond, Virginia  23298
Vanderbilt-Ingram Cancer Center, Vanderbilt UniversityNashville, Tennessee  37232