Fenretinide and Rituximab in Treating Patients With B-Cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of fenretinide and to see how well it works when given together with rituximab in treating patients with B-cell non-Hodgkin lymphoma. Drugs used in chemotherapy, such as fenretinide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Giving fenretinide together with rituximab may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety of fenretinide delivered in a 5 of 7 day regimen. (Phase I) II. To estimate the efficacy (response rates) of fenretinide + rituximab in patients with B-cell non-Hodgkin lymphoma (NHL). (Phase II) SECONDARY OBJECTIVES: I. To perform pharmacokinetic studies on patients receiving fenretinide. (Phase I) II. To determine the intratumoral concentrations of fenretinide. (Phase I) III. To evaluate the in vivo mechanism of action of fenretinide. (Phase I) IV. To identify the predictors of response to fenretinide. (Phase I) V. To estimate the response rates, positron emission tomography (PET) response, overall survival (OS), progression-free survival (PFS), time to progression (TTP), and disease-free survival (DFS) of patients treated on this study. (Phase I) VI. To estimate the overall survival (OS), progression-free survival (PFS), time to progression (TTP), disease-free survival (DFS), and PET responses of patients treated on this study. (Phase II) VII. To perform pharmacokinetic studies on patients receiving fenretinide. (Phase II) VIII. To determine the intratumoral concentration of fenretinide. (Phase II) IX. To identify the predictors of response to fenretinide and fenretinide + rituximab in B-NHL. (Phase II) X. To evaluate the in vivo mechanism of action of fenretinide in B-NHL. (Phase II) OUTLINE: This is a phase I, dose-escalation study of fenretinide followed by a phase II study. PHASE I: Patients receive fenretinide orally (PO) twice daily (BID) on days 1-5. Treatment repeats weekly for at least 4 weeks in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive fenretinide PO BID on days 1-5 in weeks 1-8 and rituximab intravenously (IV) once weekly in weeks 5-8. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Official Title
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A Phase I-II Trial of Fenretinide (4-HPR) + Rituximab in Patients With B-cell Lymphoma

Conditions
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Stage II Marginal Zone Lymphoma, Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma, B-cell Chronic Lymphocytic Leukemia, Contiguous Stage II Adult Burkitt Lymphoma, Contiguous Stage II Adult Diffuse Large Cell Lymphoma, Contiguous Stage II Adult Lymphoblastic Lymphoma, Contiguous Stage II Grade 1 Follicular Lymphoma, Contiguous Stage II Grade 2 Follicular Lymphoma, Contiguous Stage II Mantle Cell Lymphoma, Stage II Small Lymphocytic Lymphoma, Extranodal Marginal Zone B-cell Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Noncontiguous Stage II Adult Burkitt Lymphoma, Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma, Noncontiguous Stage II Adult Lymphoblastic Lymphoma, Noncontiguous Stage II Grade 1 Follicular Lymphoma, Noncontiguous Stage II Grade 2 Follicular Lymphoma, Noncontiguous Stage II Mantle Cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Splenic Marginal Zone Lymphoma, Stage I Adult Burkitt Lymphoma, Stage I Adult Diffuse Large Cell Lymphoma, Stage I Adult Hodgkin Lymphoma, Stage I Adult Lymphoblastic Lymphoma, Stage I Chronic Lymphocytic Leukemia, Stage I Grade 1 Follicular Lymphoma, Stage I Grade 2 Follicular Lymphoma, Stage I Small Lymphocytic Lymphoma, Stage II Adult Hodgkin Lymphoma, Stage II Chronic Lymphocytic Leukemia, Stage III Adult Burkitt Lymphoma, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Adult Hodgkin Lymphoma, Stage III Adult Lymphoblastic Lymphoma, Stage III Chronic Lymphocytic Leukemia, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage III Marginal Zone Lymphoma, Stage III Small Lymphocytic Lymphoma, Stage IV Adult Burkitt Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Hodgkin Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Small Lymphocytic Lymphoma, Waldenström Macroglobulinemia

Intervention / Treatment
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* Drug: fenretinide
* Drug: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a confirmed cluster of differentiation (CD) 20+ lymphoid malignancy All patients with indolent NHL (including Follicular, Marginal Zone, small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL), lymphoplasmacytoid/Waldenström's, nodular lymphocyte predominant Hodgkins) are potentially eligible Patients with Aggressive Lymphoma (including diffuse large B-cell, Burkitt's, Burkitt's-like, B-lymphoblastic) may be considered for this protocol only if unable or unwilling to receive potentially curative intensive therapy All Mantle Cell Lymphoma patients are potentially eligible The World Health Organization (WHO) classification of patient's malignancy must be provided Patients must have a Southwest Oncology Group (SWOG)/Eastern Cooperative Oncology Group (ECOG) of =< 2 Patients should have an expected survival if untreated of at least 60 days Patients must be expected to complete at least 8 weeks of therapy Serum bilirubin less than 2 times the upper limit of normal and no other serious medical condition Creatinine less than 2 times the upper limit of normal and no other serious medical condition Patients must have measurable disease defined as lesions that can be accurately measured in two dimensions by computed tomography (CT), magnetic resonance imaging (MRI), medical photograph (skin or oral lesion), plain x-ray, or other conventional technique and a greatest transverse diameter of 1 cm or greater; or palpable lesions with both diameters >= 2 cm or evaluable disease in the bone marrow; patients must have a CT of chest, abdomen, and pelvis within 28 days of enrollment; patients with evidence of adenopathy in the neck must have a CT of the neck; (Note: Patients with CLL do not need to have radiographically measurable disease as this is not required to measure response in this disease setting) All patients with an unknown prior bone marrow status or history of bone marrow involvement must have a bone marrow aspirate and biopsy within 28 days of enrollment and no intervening anticancer therapy All patients must be informed of the investigational nature of this study and have given written consent in accordance with institutional and federal guidelines Exclusion Criteria: Patients known to be human immunodeficiency virus (HIV) positive Patients with evidence of active central nervous system malignancy Pregnant or nursing women Men or women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method Concurrent anti-neoplastic therapy

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 (fenretinide, rituximab)<br>PHASE I: Patients receive fenretinide PO BID on days 1-5. Treatment repeats weekly for at least 4 weeks in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive fenretinide PO BID on days 1-5 in weeks 1-8 and rituximab IV once weekly in weeks 5-8. Treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: fenretinide<br>* Given PO<br>* Other names: McN-R-1967;Drug: rituximab<br>* Given IV<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, in Terms of Dose-limiting Toxicity (DLT) of 2 Daily Doses of Single Agent Fenretinide (Phase I) | A group of 3 patients would start treatment ast the dose of 900mg/m^2 BID, and if none of the 3 experienced a DLT, another 3 would then be treated at that dose. Dose Limiting Toxicity was defined as any related toxicity of grade 4 or 5 on or before the completion of 4 weeks of therapy. Per response evaluation criteria 1999 Cheson Response Criteria for Malignant Lymphoma (CHESON99) for target lesions assessed by either CT or MRI: Complete Response (CR): Complete disappearance of all measurable and non-measurable disease; Complete Response Unconfirmed (CRU): Complete disappearance of all measurable and non-measurable disease, with the exception of all residual nodal masses >1.5cm in Greatest Transverse Diameter (GTD) reduced by 75% in Sum of the Product of the greatest Diameters (SPD); Partial Response (PR): 50% decrease in the SPD. | Number of participants that experienced a dose-limiting toxicity | 
| Response Rates of B-Non-Hodgkin Lymphoma to the Combination of Rituximab and Fenretinide (Phase II) | The trial was stratified into rituximab-naïve and rituximab pre-treated patients, and the target response rates for these groups were expected to be 30% and 10%, respectively. The numbers reported below are subjects who achieved a response of partial response or better. | Up to 7 years |