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Phase II Study of Combination Vorinostat and Bortezomib in Patients With Relapsed and/or Refractory Non-Hodgkin Lymphoma

Phase 2
18 Years
Not Enrolling
Non-Hodgkin Lymphoma

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Trial Information

Phase II Study of Combination Vorinostat and Bortezomib in Patients With Relapsed and/or Refractory Non-Hodgkin Lymphoma

More selective and less toxic therapeutic strategies are needed to improve cure rates and
prolong survival in patients with relapsed and/or refractory non-Hodgkin Lymphoma.

Amongst the multiple new pathways recently studied two have emerged as potentially important
targets for new agents in lymphoma. These include the ubiquitin proteasome pathway and the
biochemical reactions that control histone acetylation. The first two agents in each class
to have been studied in lymphomas are: bortezomib and vorinostat. Bortezomib has been
granted FDA approval for the treatment of mantle cell lymphoma and has established activity
in a variety of B-cell lymphomas including follicular, marginal zone and diffuse large
B-cell lymphoma. Vorinostat or SAHA (suberoylanilide hydroxamic acid) has been FDA approved
for the treatment of refractory cutaneous T-cell lymphomas and has also shown activity in
other lymphomas.

Synergistic activity between vorinostat and bortezomib has been observed in different cell
lines. The proposed study will be a phase II trial of the combination of vorinostat and
bortezomib at the recommended dose-schedule in patients with recurrent and/or refractory
lymphomas, indolent and aggressive, and B or T.

Inclusion Criteria:

- Histologically confirmed non-Hodgkin Lymphoma including small lymphocytic lymphoma,
lymphoplasmacytic lymphoma, follicular center cell lymphoma, mantle cell lymphoma,
marginal zone lymphoma, diffuse large B cell lymphoma, Burkitt's lymphoma,
lymphoblastic lymphoma, anaplastic large cell lymphoma, nasal NK/T cell lymphoma,
mycosis fungoides/Sezary syndrome, angioimmunoblastic T-cell lymphoma and peripheral
T-cell lymphomas not otherwise specified

- Received 2 or > prior therapies, which may include hematopoietic cell transplant

- Received treatment with a nucleoside analog, or an alkylating agent, an anthracycline
and/or in the case of B cell lymphomas, rituximab

- Resistant disease to 2 regimens or resistant disease to at least 1 regimen after
first relapse

- Bi-dimensionally measurable disease documented within 30 days prior to enrollment.
Bidimensionally measurable disease is defined as:

- A lymph node or tumor mass that can be accurately measured in two
dimensions by CT,MRI, medical photograph (skin or oral lesion), plain X-ray, PET
scan or other conventional technique and a greatest diameter of 1 cm or >; or
palpable lesions with both diameters > 2 cm (lesion measured in 2 largest
perpendicular dimensions in millimeters)

- For the purposes of this protocol, disease should be located in an area of no
prior radiation therapy or a clear progression in an area that was previously

- Adequate organ and marrow function obtained < or = to 14 days prior to enrollment as
defined by a(n):

- ANC > or = to 1,000/microliter

- Platelet count > or = to 100,000/microliter, or > or = to 75,000/microliter if
the bone marrow is involved

- Hemoglobin level > or = to 9 g/dL

- Total bilirubin < or = to 1.5 x institutional upper limit of normality (ULN).(If
abnormal, direct bilirubin less than or equal to 1.5 x institutional ULN)

- ALT or AST < or = to 2.5 x institutional ULN (< or = to 5 x institutional ULN if
liver involvement with lymphoma)

- Serum creatinine < or = to 1.5 x institutional ULN

- Zubrod (ECOG) Performance Status of 0 or 1

- Age > than or = to 18 years

- Life expectancy > or = to 3 months as clinically determined by referring physician

- Female patient is either post menopausal, free from menses for > 2 years, surgically
sterilized or willing to use highly effective methods of contraception (i.e., a
condom in conjunction with a diaphragm, or spermicidal jelly; or oral, injectable, or
implanted birth control; or abstinence ) to prevent pregnancy throughout the study,
starting with visit 1

- Female patients of childbearing potential must have a negative serum pregnancy test
(beta-HCG) within 72 hours of enrollment and should not be nursing due to the
potential for congenital abnormalities and of harm to nursing infants due to this
treatment regimen

- Male patient agrees to use an adequate method of contraception (i.e., a condom if
female partner uses a diaphragm, spermicidal jelly; or oral, injectable, or implanted
birth control; or abstinence) for the duration of the study and for 12 weeks after
the last dose

- Patient must be able to swallow capsules

- Signed and dated IRB/ethics committee-approved informed consent before any protocol
specific screening procedures are performed

- Both men and women of all races and ethnic groups are eligible for this trial

Exclusion Criteria:

- Prior investigational therapy within 3 weeks of enrollment. Investigational therapy
is defined as treatment that is not approved for any indication

- CNS metastases, as indicated by clinical symptoms,cerebral edema, requirement for
corticosteroids and/or progressive growth (treated CNS metastases must be stable for
greater than 2 weeks prior to enrollment)

- Active second malignancy that requires treatment or that would interfere with
assessment of response

- Prior malignancy, except for adequately treated basal cell or squamous cell skin
cancer, in situ cervical cancer, or other cancer with < 5 years of documented
disease-free status

- Treatment with the following within the timeframe specified prior to enrollment:

- Chemotherapy, radiotherapy, immunotherapy (active (such as vaccines) or passive
(such as monoclonal antibodies or immunotoxins)) or major surgery < or = to 3

- Nitrosourea, or mitomycin < or = to 6 weeks

- Radioimmunotherapy (e.g. Bexxar or Zevalin) < or = to 12 weeks

- Concurrent enzyme-inducing anticonvulsant agents or valproic acid in last 4

- Prior bortezomib or any other proteasome inhibitor

- Prior vorinostat or any other histone deacetylase inhibitor

- Concurrent systemic corticosteroids (<10 mg/day of prednisone or equivalent for
adrenal insufficiency or acute allergic reactions allowed)

- Uncontrolled current illness including, but not limited to:

- Clinically or laboratory determined active infection

- Clinically limiting congestive heart failure or ejection fraction (EF) <45%

- Clinically unstable angina pectoris (or myocardial infarction within 6 months of
Day 1)

- Clinically significant cardiac arrhythmia

- Limiting pulmonary hypertension

- Pre-existing neuropathy ≥ grade 2

- Patients with pleural effusions, ascites or peripheral edema grade 2 or >


- Active viral hepatitis

- Major surgery or significant traumatic injury within 21 days prior to enrollment
(this does not apply to placement of a venous access device)

- Hypersensitivity to any of the components in vorinostat or bortezomib or agents
containing boron or mannitol

- Significant psychiatric illness/social situations that would limit compliance with
study medication and requirements of the study as determined by study MD

- Significant medical illness or abnormal laboratory finding that would, in the
investigator's judgment, increase the subject's risk by participating in this study

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the response rate of this regimen in this patient population.

Outcome Time Frame:

6 cycles

Safety Issue:


Principal Investigator

Hector A Preti, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Methodist Hospital System


United States: Institutional Review Board

Study ID:




Start Date:

June 2010

Completion Date:

Related Keywords:

  • Non-Hodgkin Lymphoma
  • non-Hodgkin Lymphoma
  • aggressive lymphoma
  • indolent lymphoma
  • B cell lymphoma
  • T cell lymphoma
  • Diffuse large B cell lymphoma
  • anaplastic large B cell lymphoma
  • lymphoblastic lymphoma
  • Burkitt's lymphoma
  • transformed follicular center cell lymphoma
  • transformed marginal zone lymphoma
  • transformed small lymphocytic lymphoma
  • grade 3 follicular center cell lymphoma
  • blastic form marginal zone lymphoma
  • transformed cutaneous T cell lymphoma
  • mycosis fungoides stage IV
  • angioimmunoblastic lymphadenopathy-like T-cell lymphoma
  • nasal NK/T cell lymphoma
  • peripheral T-cell lymphoma
  • small lymphocytic lymphoma
  • lymphoplasmacytic lymphoma
  • follicular center cell lymphoma grade 1
  • follicular center cell lymphoma grade 2
  • mantle cell lymphoma
  • marginal zone lymphoma
  • mycosis fungoides
  • Lymphoma
  • Lymphoma, Non-Hodgkin