Bortezomib, Rituximab and Combination Chemotherapy in Treating Participants With Mantle Cell Lymphoma

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of bortezomib when given with rituximab and chemotherapy drugs and to see how well they work in treating participants with 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 cyclophosphamide, doxorubicin, vincristine, dexamethasone, methotrexate, and cytarabine, 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 may work better at treating mantle cell lymphoma.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the safety and the maximum tolerated dose (MTD) of bortezomib when added to the combination of rituximab, methotrexate, and cytarabine alternating with bortezomib, rituximab-hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone (hyperCVAD) in patients with untreated aggressive mantle cell lymphoma. (Phase I) II. Evaluate the time to failure (TTF) rate following therapy with bortezomib plus rituximab-hyperCVAD alternating with bortezomib plus rituximab-high dose methotrexate/cytarabine in patients between 18 and 79 years of age with untreated aggressive mantle cell lymphoma. (Phase II) SECONDARY OBJECTIVES: I. Evaluate overall response rate, complete remission rate, overall survival, and duration of remission. (Phase I) II. Evaluate overall response rate, overall survival, and duration of remission. (Phase II) III. Evaluate toxicity of the combination regimen. (Phase II) IV. Correlate outcome with pretreatment markers. (Phase II) OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II study. Participants receive Drug Combination I during courses 1, 3, 5, and 7 (if needed) and Drug Combination II during courses 2, 4, 6, and 8 (if needed) in the absence of disease progression or unacceptable toxicity. Drug Combination I: Participants receive rituximab intravenously (IV) over 6 hours on day 1, cyclophosphamide IV over 3 hours twice daily (BID) on days 2-4, doxorubicin IV over 15-30 minutes on day 5, vincristine IV over 15-30 minutes on days 5 and 12, dexamethasone orally (PO) or IV on days 2-5 and 12-15, and bortezomib IV over a few seconds after the first dose of cyclophosphamide and immediately after vincristine and doxorubicin have been given on day 5. Drug Combination II: Participants receive rituximab IV over 6 hours on day 1, methotrexate IV over 24 hours on day 2, and cytarabine IV over 2 hours every 12 hours on days 3-4. After completion of study treatment, participants are followed up every 3 months for 1 year, every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Official Title
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Phase I/II Study of Bortezomib (VELCADE) Plus Rituximab-HyperCVAD Alternating With Bortezomib Plus Rituximab-High Dose Methotrexate/Cytarabine in Patients With Untreated Aggressive Mantle Cell Lymphoma

Conditions
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Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Doxorubicin
* Drug: Methotrexate
* Biological: Rituximab
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of previously untreated nodular or diffuse mantle cell lymphoma and their blastoid cytologic variant. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Serum bilirubin < 1.5 mg/dl and serum creatinine < 2.0 mg/dl within 14 days before enrollment (unless higher levels are due to lymphoma). Platelet count > 100,000/mm^3 within 14 days before enrollment (unless due to lymphoma). Absolute neutrophil count (ANC) > 1,000/mm^3 within 14 days before enrollment (unless due to lymphoma). Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multigated acquisition (MUGA). Patients must be willing to receive transfusions of blood products. Voluntary written Institutional Review Board (IRB)-approved 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. Female subject is either post-menopausal for 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 birth control, at the same time (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) 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. Male subject, even if surgically sterilized (ie, status post vasectomy) agrees 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. Exclusion Criteria: Human immunodeficiency virus (HIV) infection. Central nervous system (CNS) involvement. Co-morbid medical or psychiatric illnesses that preclude treatment with intense dose chemotherapy. Concurrent or previous malignancy with < 90% probability of survival at 5 years. Patient has >= grade 2 peripheral neuropathy within 14 days before enrollment. 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 electrocardiography (ECG) abnormality at screening has to be documented by the investigator as not medically relevant. Patient has hypersensitivity to bortezomib, boron or mannitol. Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Participating 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy)<br>Participants receive Drug Combination I during courses 1, 3, 5, and 7 (if needed) and Drug Combination II during courses 2, 4, 6, and 8 (if needed) in the absence of disease progression or unacceptable toxicity. Drug Combination I: Participants receive rituximab IV over 6 hours on day 1, cyclophosphamide IV over 3 hours BID on days 2-4, doxorubicin IV over 15-30 minutes on day 5, vincristine IV over 15-30 minutes on days 5 and 12, dexamethasone PO or IV on days 2-5 and 12-15, and bortezomib IV over a few seconds after the first dose of cyclophosphamide and immediately after vincristine and doxorubicin have been given on day 5. Drug Combination II: Participants receive rituximab IV over 6 hours on day 1, methotrexate IV over 24 hours on day 2, and cytarabine IV over 2 hours every 12 hours on days 3-4. | Drug: Bortezomib<br>* Given IV<br>* Other names: Velcade;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: Visumetazone;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Bortezomib (Phase I) | Determine the safety and the maximum tolerated dose (MTD) of bortezomib when added to the combination of rituximab, methotrexate, and cytarabine alternating with bortezomib, rituximab-hyperCVAD in patients with untreated aggressive mantle cell lymphoma. | Cycle 1 Day 1 - End of Cycle 2 up to 60 days. | 
| Time to Failure (Phase II) | Failure will be defined as recurrence/progression of disease or death from either disease or toxicity. Bayesian toxicity monitoring schema will be used to monitor severe toxicity profile in combined therapy. Severe toxicity is defined as at least two episodes of neutropenic fever during treatment courses. | First date of diagnosis up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Response Rate | Response rate is determined by CT scans of the chest, abdomen, and pelvis, unilateral BM biopsy and aspirate with lymphoma markers (if initially positive) and colonoscopy/endoscopy if applicable. | Up to 5 years | 
| Overall Survival | Overall survival is the time in number of months from start of study treatment to date of death due to any cause. | Date of diagnosis to last known date of survival, up to 5 years |