Bortezomib and Lenalidomide in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

Study Overview
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Brief Summary
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This phase II trial studies how well bortezomib and lenalidomide work in treating patients with mantle cell lymphoma that has come back after a period of improvement (refractory) or is not responding to treatment (refractory). Bortezomib may also stop the growth of cancer cells by blocking some proteins needed for cell growth. Lenalidomide may stimulate the immune system to kill cancer cells and may also block the growth of new blood vessels necessary for cell growth. Giving bortezomib with lenalidomide may be an effective treatment for relapsed or refractory mantle cell lymphoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the overall response (complete response [CR] and partial response [PR]) rate and the complete response (CR) rate to bortezomib + lenalidomide therapy in patients with relapsed or refractory mantle cell lymphoma. SECONDARY OBJECTIVES: I. To determine the time to progression after therapy with bortezomib + lenalidomide in patients with relapsed or refractory mantle cell lymphoma. II. To determine the disease-free survival and overall survival after therapy with bortezomib + lenalidomide in patients with relapsed or refractory mantle cell lymphoma. OUTLINE: Patients receive induction therapy comprising bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide orally (PO) once daily (QD) on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib IV on days 1 and 8 and lenalidomide PO QD on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually for 2 years.

Official Title
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A Phase II Trial of Bortezomib (NSC #681239) + Lenalidomide (Revlimid™, CC-5013) (NSC #703813) for Relapsed/Refractory Mantle Cell Lymphoma

Conditions
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Recurrent Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Bortezomib
* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented mantle cell lymphoma, with the following immunophenotypic characteristics: cluster of differentiation (CD)5+, CD23-, cyclin D1+; this may be from an initial diagnostic biopsy, or one obtained at time of relapse Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies; fine needle aspirates are not acceptable Failure to submit pathology specimens within 60 days of patient registration will be considered a major protocol violation Institutional flow cytometry or immunohistochemistry must confirm CD5 antigen expression, lack of CD23 antigen expression, and expression of cyclin D1 Prior therapy with at least one regimen, which may have been single agent or multi-agent, and consisted of traditional cytotoxic agents and/or biologic agents; patient may not have received prior bortezomib or lenalidomide therapy; patient must have progressive disease or refractory disease following that initial regimen(s); refractory disease will be defined as stable disease (SD) or progressive disease (PD) as best response to prior therapy, or CR or PR as initial response followed by disease progression within 6 months Prior autologous, but not allogeneic, stem cell transplant is allowed No corticosteroids within two weeks prior to study, except for maintenance therapy for a non-malignant disease; maintenance therapy dose may not exceed 20 mg/day prednisone or equivalent No prior radioimmunotherapy within 12 months of study entry No >= grade 3 peripheral neuropathy within a month prior to study entry Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable; any tumor mass > 1 cm by physical exam, computed tomography (CT), magnetic resonance imaging (MRI), or conventional radiograph is acceptable; lesions that are considered non-measurable include the following: Bone lesions (lesions, if present, should be noted) Ascites Pleural/pericardial effusion Lymphangitis cutis or pulmonis Bone marrow (involvement by non-Hodgkin lymphoma should be noted) No known central nervous system (CNS) involvement by lymphoma Patients with human immunodeficiency virus (HIV) infection are eligible, provided they meet the following: CD4+ cell count > 350/mm^3; treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50 copies/mm^3; no history of acquired immunodeficiency syndrome (AIDS)-defining conditions or other HIV-related illnesses; no concurrent zidovudine or stavudine Non-pregnant and non-nursing; females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to registration; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure; documentation of counseling is required on Cancer and Leukemia Group B (CALGB) form S-041 Patients with a recent history (within 3 months of study entry) of deep vein thrombosis (DVT)/pulmonary embolism (PE) are not eligible; patients with a distant history (greater than 3 months before study entry) of DVT/PE are eligible, but must receive either prophylactic aspirin or low molecular weight heparin, unless contraindicated Left ventricular ejection fraction (LVEF) >= 45% by multigated acquisition (MUGA) scan or echocardiogram No New York Heart Association class III or class IV congestive heart failure at study entry No myocardial infarction within the past 6 months of study entry No known positivity for hepatitis A, B, or C Absolute neutrophil count (ANC) >= 1,000/uL (>= 500/uL if marrow involvement) Platelets >= 75,000/uL Creatinine =< 1.5 x upper limit of normal (ULN) (unless attributable to non-Hodgkin's lymphoma) and estimated creatinine clearance >= 30 mL/min (patients on dialysis are not eligible) Total bilirubin =< 2 x ULN (unless attributable to non-Hodgkin's lymphoma and Gilbert's disease) Urine (U)-human chorionic gonadotropin (HCG) or serum HCG negative

Ages Eligible for Study
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Minimum Age: 18 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 (bortezomib, lenalidomide)<br>Patients receive induction therapy comprising bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide PO QD on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib IV on days 1 and 8 and lenalidomide PO QD on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity. | Drug: Bortezomib<br>* Given IV<br>* Other names: Velcade;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Overall Response Defined as Complete Response and Partial Response | Response is assessed by investigator according to International Working Group (IWG) criteria. A complete response requires disappearance of all evidence of disease. A partial response is a >/= 50% decrease in the sum of products of 6 largest dominant nodes or nodal masses as well as for splenic and hepatic nodules. No increase in size of nodes, liver or spleen and no new sites of disease. | Duration of treatment (assessed up to 6 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Number of participants who experienced a maximum grade 3, 4 or 5 adverse event. The grading scales found in the revised NCI CTCAE version 4.0 was utilized for adverse event reporting | Duration of Treatment (up to 6 years) | 
| Time to Progression | Time to progression (TTP) is defined as the time from study entry until progression or death due to any cause. The median TTP with 95% CI was estimated using the Kaplan-Meier method. | Assessed up to 6 years | 
| Overall Survival | Overall survival (OS) is defined as the time from study entry until death. The median OS with 95% CI was estimated using the Kaplan-Meier method.. | Assessed up to 6 years |