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Bortezomib and Vorinostat as Maintenance Therapy After Autologous Transplant for Non-Hodgkin's Lymphoma Using R-BEAM or BEAM Conditioning Transplant Regimen


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Anaplastic Large Cell Lymphoma, Contiguous Stage II Adult Diffuse Large Cell Lymphoma, Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma, Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma, Contiguous Stage II Grade 1 Follicular Lymphoma, Contiguous Stage II Grade 2 Follicular Lymphoma, Contiguous Stage II Grade 3 Follicular Lymphoma, Contiguous Stage II Mantle Cell Lymphoma, Grade 1 Follicular Lymphoma, Grade 2 Follicular Lymphoma, Grade 3 Follicular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma, Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma, Noncontiguous Stage II Grade 1 Follicular Lymphoma, Noncontiguous Stage II Grade 2 Follicular Lymphoma, Noncontiguous Stage II Grade 3 Follicular Lymphoma, Noncontiguous Stage II Mantle Cell Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Stage I Adult Diffuse Large Cell Lymphoma, Stage I Adult Diffuse Mixed Cell Lymphoma, Stage I Adult Diffuse Small Cleaved Cell Lymphoma, Stage I Adult T-cell Leukemia/Lymphoma, Stage I Cutaneous T-cell Non-Hodgkin Lymphoma, Stage I Grade 1 Follicular Lymphoma, Stage I Grade 2 Follicular Lymphoma, Stage I Grade 3 Follicular Lymphoma, Stage I Mantle Cell Lymphoma, Stage I Mycosis Fungoides/Sezary Syndrome, Stage II Adult T-cell Leukemia/Lymphoma, Stage II Cutaneous T-cell Non-Hodgkin Lymphoma, Stage II Mycosis Fungoides/Sezary Syndrome, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Adult Diffuse Mixed Cell Lymphoma, Stage III Adult Diffuse Small Cleaved Cell Lymphoma, Stage III Adult T-cell Leukemia/Lymphoma, Stage III Cutaneous T-cell Non-Hodgkin Lymphoma, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage III Mycosis Fungoides/Sezary Syndrome, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult T-cell Leukemia/Lymphoma, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Mycosis Fungoides/Sezary Syndrome

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Trial Information

Bortezomib and Vorinostat as Maintenance Therapy After Autologous Transplant for Non-Hodgkin's Lymphoma Using R-BEAM or BEAM Conditioning Transplant Regimen


PRIMARY OBJECTIVES:

I. Assess toxicities of combining vorinostat and bortezomib as maintenance therapy after
ASCT for NHL.

SECONDARY OBJECTIVES:

I. Ability to complete planned therapy.

II. Time to disease progression and event-free survival.

III. Overall survival.

OUTLINE:

All patients receive carmustine intravenously (IV) over 3 hours on day -7; cytarabine IV
twice daily over 3 hours and etoposide IV twice daily over 2 hours on days -6 to -3; and
melphalan IV over 30 minutes on day -2. Only patients with CD20+ lymphoma receive additional
rituximab IV on days -19 and -12. Patients undergo ASCT on day 0. Patients then receive
bortezomib IV on days 2 and 8 and vorinostat orally (PO) once daily on days 1-14 of 28-day
cycle. Treatment with bortezomib and vorinostat repeats for total of 12 cycles in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for at least 2 years.


Inclusion Criteria:



- Inclusion Criteria for Autologous Transplant:

- Diagnosis of NHL, transformed B-cell lymphoma, follicular lymphoma, mantle cell
lymphoma, diffuse large B-cell or T-cell lymphoma, and deemed a candidate for
autologous transplant

- American Heart Association Class I: patients with cardiac disease but without
resulting limitation of physical activity; ordinary physical activity does not cause
undue fatigue, palpitation, dyspnea, or anginal pain; additionally, patients > 60
years of age must have a left ventricular ejection fraction of at least >= 40%
demonstrated by multi gated acquisition scan (MUGA) or echocardiogram (ECG)

- Total bilirubin (TB) =< 1.5 mg/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3x the upper
limit of normal (ULN)

- Creatinine clearance (CrCL) (calculated creatinine clearance is permitted) > 40
mL/min

- Diffusing capacity of carbon monoxide (DLCO), forced expiratory volume in one second
(FEV1), and forced vital capacity (FVC) >= 50% of predicted (corrected for
hemoglobin)

- Autologous graft with a minimum of >= 3.0 x 10^6 CD34+ cells/kg; not CD34 selected

- Signed informed consent

- Female patients of childbearing potential has a negative serum pregnancy test
beta-human chorionic gonadotropin (hCG)

- Female patient is either post menopausal, free from menses for >= 2 years, surgically
sterilized, or willing to use 2 adequate barrier methods of contraception to prevent
pregnancy or agrees to abstain from heterosexual activity throughout the study

- Male patient agrees to use an adequate method of contraception for the duration of
the study

- Inclusion Criteria for Maintenance Therapy:

- 30-120 days post ASCT for NHL

- CrCL >= 40 ml/min

- Platelets (PLT) >= 75,000 cells/mm^3 for 5 days after recovery from ASCT nadir

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 for 5 days after recovery from
ASCT nadir

- TB =< 1.5 x ULN

- AST/ALT =< 2.5 x ULN

Exclusion Criteria:

- Exclusion Criteria for Transplant:

- Karnofsky performance score < 70%

- Uncontrolled bacterial, viral, or fungal infection (currently taking medication and
with progression or no clinical improvement)

- Pregnant or breastfeeding

- Fertile men and women unwilling to use contraceptive techniques from the time of
transplant until one month post maintenance therapy

- Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT)

- Patients with evidence of myelodysplastic syndromes (MDS)/acute myeloid leukemia
(AML) or abnormal cytogenetics analysis indicative of MDS on the pre-transplant bone
marrow examination

- Prolonged QTC on electrocardiogram (EKG)

- Poorly-controlled diabetes mellitus (DM)

- >= grade 2 peripheral neuropathy

- Prior history of human immunodeficiency virus (HIV) positivity or known history of
hepatitis B or C

- Previous history of hypersensitivity to Bortezomib, boron, or mannitol; known
hypersensitivity to the components of study drug or its analogs

- Require therapeutic anticoagulation treatment, especially with coumadin

- Patient who has had chemotherapy, radiotherapy, or biological therapy, within 30 days
(42 days for nitrosoureas or mitomycin C) or who has not recovered from adverse
events due to agents administered more than 30 days earlier

- Patient is currently participating or has participated in a study with an
investigational compound or devise within 30 days of initial dosing with study
drug(s)

- Patient had prior treatment with an histone deacetylase (HDAC) inhibitor (e.g.,
romidepsin [Depsipeptide], NSC-630176, MS 275, LAQ-824, belinostat [PXD-101], LBH589,
MGCD0103, CRA024781, etc); patients who have received compounds with HDAC
inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not
enroll in this study; patients who have received such compounds for other
indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout
period

- History of central nervous system (CNS) disease

- Symptomatic ascites or pleural effusions

- Patient has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- Patient is, at the time of signing informed consent, a regular user (including
"recreational use") of any illicit drugs, substance abuse or had a recent history
(within the last year) of drug or alcohol abuse

- Patient with a history of a prior malignancy with the exception of complete resection
of basal cell carcinoma or squamous cell carcinoma or an in situ malignancy;
adequately treated localized prostate carcinoma with prostate-specific antigen (PSA)
< 1.0; or who has undergone potentially curative therapy with no evidence of disease
for five years, and/or who is deemed at low risk for recurrence by his/her treating
physician

- Patient has a history or current evidence of any condition, therapy, or lab
abnormality that might confound the results of the study, interfere with the
patient's participation for the full duration of the study or is not in the best
interest of the patient to participate

- Patient has a history of a gastrointestinal surgery or other procedures that might,
in the opinion of the investigator, interfere with the absorption or swallowing of
the study drugs

- Exclusion Criteria for Maintenance Therapy:

- >= grade 2 peripheral neuropathy within 14 days before beginning maintenance therapy

- Prolonged QTC

- Poorly controlled diabetes mellitus (DM)

- Myocardial infarction (MI) with ASCT or developed dilated cardiomyopathy with ASCT

- Untreated systemic infection

- Potassium (K) and magnesium (Mg) < normal limits of adequate supplementation

- Patient had MI within 6 months prior to enrollment or has New York Heart Association
(NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
conduction system abnormalities; prior to study entry, any ECG abnormality at
screening must be documented by the investigator as not medically relevant

- Patient has hypersensitivity to VELCADE, boron, or mannitol

- Female subject is pregnant or lactating; confirmation that the subject is not
pregnant must be established by a negative serum beta-hCG pregnancy test result
obtained during screening; pregnancy testing is not required for postmenopausal or
surgically sterilized women

- Female patients who are lactating or have a positive serum pregnancy test during the
screening period, or a positive urine pregnancy test on Day 1 before first dose of
study drug, if applicable

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

- Participation in clinical trials with other investigational agents not included in
this trial, within 14 days of the start of this trial and throughout the duration of
this trial

- Radiation therapy within 3 weeks before randomization; enrollment of subjects who
require concurrent radiotherapy (which must be localized in its field size) should be
deferred until the radiotherapy is completed and 3 weeks have elapsed since the last
date of therapy

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity of maintenance therapy with bortezomib and vorinostat

Outcome Description:

Grade of toxicity will be per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.

Outcome Time Frame:

3 months

Safety Issue:

Yes

Principal Investigator

Leona Holmberg

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Institutional Review Board

Study ID:

2292.00

NCT ID:

NCT00992446

Start Date:

December 2009

Completion Date:

Related Keywords:

  • Anaplastic Large Cell Lymphoma
  • Contiguous Stage II Adult Diffuse Large Cell Lymphoma
  • Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma
  • Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
  • Contiguous Stage II Grade 1 Follicular Lymphoma
  • Contiguous Stage II Grade 2 Follicular Lymphoma
  • Contiguous Stage II Grade 3 Follicular Lymphoma
  • Contiguous Stage II Mantle Cell Lymphoma
  • Grade 1 Follicular Lymphoma
  • Grade 2 Follicular Lymphoma
  • Grade 3 Follicular Lymphoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma
  • Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
  • Noncontiguous Stage II Grade 1 Follicular Lymphoma
  • Noncontiguous Stage II Grade 2 Follicular Lymphoma
  • Noncontiguous Stage II Grade 3 Follicular Lymphoma
  • Noncontiguous Stage II Mantle Cell Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Stage I Adult Diffuse Large Cell Lymphoma
  • Stage I Adult Diffuse Mixed Cell Lymphoma
  • Stage I Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage I Adult T-cell Leukemia/Lymphoma
  • Stage I Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage I Grade 1 Follicular Lymphoma
  • Stage I Grade 2 Follicular Lymphoma
  • Stage I Grade 3 Follicular Lymphoma
  • Stage I Mantle Cell Lymphoma
  • Stage I Mycosis Fungoides/Sezary Syndrome
  • Stage II Adult T-cell Leukemia/Lymphoma
  • Stage II Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage II Mycosis Fungoides/Sezary Syndrome
  • Stage III Adult Diffuse Large Cell Lymphoma
  • Stage III Adult Diffuse Mixed Cell Lymphoma
  • Stage III Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage III Adult T-cell Leukemia/Lymphoma
  • Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage III Grade 1 Follicular Lymphoma
  • Stage III Grade 2 Follicular Lymphoma
  • Stage III Grade 3 Follicular Lymphoma
  • Stage III Mantle Cell Lymphoma
  • Stage III Mycosis Fungoides/Sezary Syndrome
  • Stage IV Adult Diffuse Large Cell Lymphoma
  • Stage IV Adult Diffuse Mixed Cell Lymphoma
  • Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage IV Adult T-cell Leukemia/Lymphoma
  • Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Grade 3 Follicular Lymphoma
  • Stage IV Mantle Cell Lymphoma
  • Stage IV Mycosis Fungoides/Sezary Syndrome
  • Autologous stem cell transplant NHL maintenance therapy
  • Leukemia
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, Large-Cell, Anaplastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109