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Bortezomib and Vorinostat as Maintenance Therapy After Autologous Stem Cell Transplant in Treating Patients With Non-Hodgkin Lymphoma

Information source: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Adult Diffuse Large B-Cell Lymphoma; B-Cell Non-Hodgkin Lymphoma; Follicular Lymphoma; Mantle Cell Lymphoma; T-Cell Non-Hodgkin Lymphoma

Intervention: Rituximab (Drug); Carmustine (Drug); Cytarabine (Drug); Etoposide (Drug); Melphalan (Drug); Bortezomib (Drug); Vorinostat (Drug); Autologous Hematopoietic Stem Cell Transplantation (Procedure)

Phase: Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
Leona Holmberg, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Summary

This phase II trial studies the side effects and how well bortezomib and vorinostat work in treating patients with non-Hodgkin lymphoma (NHL) after patients' own stem cell (autologous) transplant. Bortezomib and vorinostat in the laboratory may stop the growth of lymphoma cells and make them more likely to die by blocking some of the enzymes needed for cell growth. Giving bortezomib together with vorinostat after an autologous stem cell transplant may thus kill lymphoma cells that remain after transplant.

Clinical Details

Official title: Bortezomib* and Vorinostat as Maintenance Therapy After Autologous Transplant for Non-Hodgkin Lymphoma Using R-BEAM or BEAM Conditioning Transplant Regimen

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

Primary outcome: Toxicity of maintenance therapy with bortezomib and vorinostat

Secondary outcome: Time to disease progression

Detailed description: PRIMARY OBJECTIVES: I. Assess toxicities of combining vorinostat and bortezomib as maintenance therapy after autologous stem cell transplant (ASCT) for NHL. SECONDARY OBJECTIVES: I. Ability to complete planned therapy. II. Time to disease progression, event-free survival. III. Overall survival. OUTLINE:

All patients receive carmustine intravenously (IV) over 3 hours on day - 7; cytarabine IV

twice daily (BID) over 3 hours and etoposide IV BID over 2 hours on days - 6 to -3; and

melphalan IV over 30 minutes on day - 2. Only patients with history of cluster of

differentiation (CD)20+ NHL 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 (QD) on days 1-14. Treatment with bortezomib and vorinostat repeats for total of 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for at least 2 years.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: INCLUSION CRITERIA FOR AUTOLOGOUS TRANSPLANT

- Diagnosis of non-Hodgkin's lymphoma, 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 =< 1. 5 mg/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x the upper

limit of normal

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

mL/min

- Diffusing capacity of the lung for 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 postmenopausal, 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

- Total bilirubin (TB) =< 1. 5 x upper limit of normal (ULN)

- AST/ALT =< 2. 5 x ULN

Exclusion Criteria: EXCLUSION CRITERIA FOR AUTOLOGOUS 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 corrected QT interval (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 laboratory

(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 DM

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

- Untreated systemic infection

- Potassium (K) and magnesium (Mg) >= grade 2 toxicity

- Patient had myocardial infarction 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 (bortezomib), boron, or mannitol

- Female subject is pregnant or lactating; confirmation that the subject is not

pregnant must be established by a negative serum beta-human chorionic gonadotropin (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

Locations and Contacts

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
Leona A. Holmberg, Phone: 206-667-6447
Leona A. Holmberg, Principal Investigator
Additional Information

Starting date: December 2009
Last updated: June 15, 2015

Page last updated: August 23, 2015

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