Bortezomib, Rituximab, and Combination Chemotherapy Followed By Maintenance Bortezomib or Observation in Treating Patients with Previously Untreated Mantle Cell Lymphoma

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IITreatment18 and over05-C-0170
NCI-2013-01594, NCT00131976, P6450, NCI-05-C-0170, NCI-6450, NCT00114738

Trial Description

Summary

This randomized phase II trial studies how well bortezomib, rituximab, and combination chemotherapy followed by maintenance bortezomib or observation works in treating patients with untreated mantle cell lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as etoposide, doxorubicin hydrochloride, vincristine sulfate, and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bortezomib, rituximab, and combination chemotherapy, followed by maintenance therapy may be an effective treatment for previously untreated mantle cell lymphoma.

Further Study Information

PRIMARY OBJECTIVES:

I. Determine the progression free survival (PFS) and overall survival (OS) of dose-adjusted etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, rituximab, and bortezomib (DA-EPOCH-RB) followed by bortezomib maintenance versus observation.

SECONDARY OBJECTIVES:

I. Determine response to bortezomib pre-DA-EPOCH-RB in “window of opportunity.”

II. Determine response and toxicity of DA-EPOCH-RB.

III. Determine response and PFS of bortezomib at disease progression in the observation arm.

IV. Compare time to non-protocol treatment in the maintenance versus observation arms.

V. Assess effects of bortezomib on mantle cell lymphoma by microarray, proteomics and

genomic methylation microarrays.

VI. Correlate microarray, genomic methylation and proteomic findings with clinical outcomes.

OUTLINE:

PART A: Patients receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Patients receive 1 course lasting 21 days in the absence of disease progression or unacceptable toxicity.

PART B: Patients receive bortezomib IV over 3-5 seconds on days 1 and 4, prednisone orally (PO) twice daily (BID) on days 1-5, and rituximab IV over 90 minutes on day 1. Patients also receive etoposide IV continuously, doxorubicin hydrochloride IV continuously, and vincristine sulfate IV continuously on days 1-4, and cyclophosphamide IV over 30-60 minutes on day 5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving at least partial response (PR) after Part B are randomized to 1 of 2 arms.

PART C:

ARM I: Beginning 8-12 weeks after completion of DA-EPOCH-RB, patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 56 days for up to 18 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo clinical observation in the absence of disease progression or unacceptable toxicity. Patients achieving disease progression receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 28 days for up to 18 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 2 years and then yearly thereafter.

Eligibility Criteria

Inclusion Criteria:

Male subject even if surgically sterilized (i.e., status post vasectomy) must agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study treatment, or agree to completely abstain from heterosexual intercourse

No myocardial infarction within 6 months prior to enrollment or 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 electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant

No history of hypersensitivity to bortezomib, boron or mannitol

Female subject is either post-menopausal at least 1 year before the screening visit or surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) at the same time, from the time of signing the informed consent through 30 days after the last dose of study treatment, or agree to completely abstain from heterosexual intercourse; female subject is not pregnant or breast-feeding; 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 post-menopausal or surgically sterilized women

Ability to give voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care

Platelets > 75,000 unless impairment due to organ involvement by lymphoma

Absolute neutrophil count (ANC) > 1000 unless impairment due to organ involvement by lymphoma

Bilirubin =< 1.5 mg/dl (total) except < 5 mg/dl in patients with Gilbert’s syndrome as defined by > 80% unconjugated

No prior treatment except for local radiation or a short course of steroids for control of symptoms; 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

Human immunodeficiency virus (HIV) antibody negative

No serious medical or psychiatric illness likely to interfere with participation in this clinical study

Patient has not received other investigational drugs with 14 days before enrollment

Serum creatinine =< 1.5 mg/dl or creatinine clearance > 50 ml/min

No grade 2 >= peripheral neuropathy within 14 days before enrollment

All stages of disease

Diagnosis of mantle cell lymphoma (confirmed at National Cancer Institute [NCI]); all variants are eligible

Eastern Cooperative Oncology Group (ECOG) performance status =< 3

No invasive tumors within the last 5 years unless confined to an organ (e.g. prostate or thyroid cancer) and treated with curative therapy (e.g. surgery and/or radiation); please note, there must be no evidence of the prior malignancy using standard criteria to evaluate the specific prior malignancy

No known involvement of central nervous system by lymphoma

Exclusion for fludeoxyglucose F 18 (FDG) scan is anyone exceeding the weight limit of the scanner (350 lb)

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

NCI - Center for Cancer Research

  • National Cancer Institute
Wyndham Hopkins Wilson, Principal Investigator

Trial Sites

U.S.A.

Maryland
Bethesda

Mark O Hatfield-Warren Grant Magnuson Clinical Center

Wyndham Hopkins Wilson
Ph: 301-435-2415
Email: wilsonw@mail.nih.gov

Wyndham Hopkins Wilson
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00114738

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.