Velcade, Nipent, Rituxan (VNR) in Subjects With Relapsed Follicular, Marginal Zone, and Mantle Cell Lymphoma

Study Overview
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Brief Summary
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This is a phase 1/2 Study of VELCADE (bortezomib), Nipent (pentostatin), and Rituxan (rituximab) (VNR) in Subjects with Relapsed Follicular, Marginal Zone, and Mantle Cell Lymphoma.

Detailed Description
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Number of Subjects: During the Phase 1 part of the study as many as 15 subjects may be enrolled, based on the dose escalation scheme; the actual number of subjects enrolled will depend on the dose level at which the maximum tolerated dose (MTD) is established. During the Phase 2 part of the study, approximately 15 subjects will be enrolled in order to obtain a total 30 response-evaluable subjects. Study Objectives: The primary objectives of this study are: • Assess the CR and ORR following treatment with VELCADE (bortezomib), Nipent (pentostatin) and Rituxan (rituximab) (VNR) in subjects with follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) who have relapsed or been refractory after receiving at least 1 prior therapy. The secondary objectives of this study are to: Determine the MTD of VELCADE and Nipent in combination with Rituxan (VNR) in subjects with follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) who have relapsed or been refractory after receiving at least 1 prior therapy Evaluate the safety and tolerability of VNR Determine the time to response Determine duration of response Determine the time to progression (TTP) Determine the progression free survival (PFS) rate Determine the 1-year survival Determine overall survival (OS)

Official Title
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Phase 1/2 Study of VELCADE (Bortezomib), Nipent (Pentostatin), and Rituxan (Rituximab) (VNR) in Subjects With Relapsed Follicular, Marginal Zone, and Mantle Cell Lymphoma

Conditions
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Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: MTD of Velcade, Nipent and Rituxan established in Part 1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written informed consent. Male or female subject 18 years of age and older Karnofsky Performance Status (KPS) score of 50%. ECOG Performance Status score greater than 2. Histologically confirmed follicular Grade 1-3a, marginal zone or mantle cell NHL. Relapsed or progressive disease after at least 1 prior chemotherapy requiring treatment. Bi-dimensionally measurable disease with at least 1 lesion 2 cm in a single dimension Hematologic, hepatic, and renal function parameters. Recovered fully from any significant toxicity associated with prior surgery, radiation treatments, chemotherapy, biological therapy, autologous bone marrow or stem cell transplant, or investigational drugs Expected survival of 3 months Accepted birth control methods during treatment and for 12 months after completion of treatment. Exclusion Criteria: Follicular lymphoma Grade 3b History of allergy to any of the study medications, their analogues, murine proteins, or excipients in the various formulations Grade 2 peripheral neuropathy or clinical examination within 14 days before enrollment Serum creatinine 2.5 mg/dL within 14 days before enrollment. Absolute neutrophil count (ANC) < 1,000/L, platelet count < 70,000/L within 14 days before enrollment Aspartate transaminase (AST [SGOT]) and alanine transaminase (ALT/SGPT]) > 2 x the upper limit of normal (ULN), total bilirubin > 3 ULN Rituxan refractory or refractory to anti-CD20 radioimmunotherapy (no response to prior Rituxan or prior Rituxan-containing regimen, or a response with a TTP of less than 6 months) Cancer radiotherapy, biological therapy, or chemotherapy within 3 weeks prior to Study Day 1 (6 weeks if nitrosurea or mytomycin-C) Prior lymphoma vaccine therapy within 12 months to Study Day 1 Prior antibody therapy for lymphoma (including radioimmunotherapy) within 6 months prior to Study Day 1 Autologous bone marrow or stem cell transplant within 6 months prior to Study Day 1 Known history of hepatitis or hepatic disease. Presence of central nervous system (CNS) lymphoma Known history of HIV infection or AIDS Histologic transformation (Follicular or Marginal zone to diffuse large B cell lymphoma [DLBCL] Presence of pleural or peritoneal effusion with positive cytology for lymphoma Another primary malignancy requiring active treatment Serious non-malignant disease (e.g., congestive heart failure [CHF], hydronephrosis); active uncontrolled bacterial, viral, or fungal infections; or other conditions (including psychiatric), which would compromise protocol objectives n the opinion of the Investigator and/or Sponsor New York Heart Association Class III or IV (Appendix D) cardiac disease Major surgery, other than diagnostic surgery, within 4 weeks prior to Study Day 1 Female subject who is pregnant or currently breast-feeding Received other investigational drugs with 14 days before enrollment Hypersensitivity to bortezomib, pentostatin, rituximab, boron or mannitol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: establish MTD<br>Part 1 consists of dosing to determine maximum tolerated dose (MTD) and dose limiting toxicity (DLT). | Drug: MTD of Velcade, Nipent and Rituxan established in Part 1<br>* One of the following dose levels will be chosen and used in Part 2: (VAN1) VA= 1.3 mg/m2 IV Days 1, 4, 8, 11 N1= 2 mg/mg2 IV Days 1, 8 375 mg/m2 IV Day 1 (VAN2) VA= 1.3 mg/m2 IV Days 1, 4, 8, 11 N1= 4 mg/mg2 IV Days 1, 8 375 mg/m2 IV Day 1 (VBN1) VA= 1.5 mg/m2 IV Days 1, 4, 8, 11 N1= 2 mg/mg2 IV Days 1, 8 375 mg/m2 IV Day 1 (VBN2) VA= 1.5 mg/m2 IV Days 1, 4, 8, 11 N1= 4 mg/mg2 IV Days 1, 8 375 mg/m2 IV Day 1<br>|
| Experimental: Part 2: The MTD from Part 1<br>During the Phase 2 part of the study, approximately 24 additional subjects will be enrolled in order to obtain a total of 30 response-evaluable subjects treated at the maximum tolerated dose. | Drug: MTD of Velcade, Nipent and Rituxan established in Part 1<br>* One of the following dose levels will be chosen and used in Part 2: (VAN1) VA= 1.3 mg/m2 IV Days 1, 4, 8, 11 N1= 2 mg/mg2 IV Days 1, 8 375 mg/m2 IV Day 1 (VAN2) VA= 1.3 mg/m2 IV Days 1, 4, 8, 11 N1= 4 mg/mg2 IV Days 1, 8 375 mg/m2 IV Day 1 (VBN1) VA= 1.5 mg/m2 IV Days 1, 4, 8, 11 N1= 2 mg/mg2 IV Days 1, 8 375 mg/m2 IV Day 1 (VBN2) VA= 1.5 mg/m2 IV Days 1, 4, 8, 11 N1= 4 mg/mg2 IV Days 1, 8 375 mg/m2 IV Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR following treatment with VELCADE(bortezomib)/Nipent(pentostatin/Rituxan (rituximab)(VNR) in subjects with follicular lymphoma(FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL)relapsed or refractory after at least 1 prior therapy | Study Days 1, 4, 8, 11 of 6 cycles (up to 3 weeks each) and Days 63/126, then Study Months 6, 9, 12, 15, 18, 21, 24, 30, 36, 42 and 48 | up to 48 months | 
| ORR following treatment with VELCADE(bortezomib)/Nipent(pentostatin/Rituxan (rituximab)(VNR) in subjects with follicular lymphoma(FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL)relapsed or refractory after at least 1 prior therapy | Study Days 1, 4, 8, 11 of 6 cycles (up to 3 weeks each) and Days 63/126, then Study Months 6, 9, 12, 15, 18, 21, 24, 30, 36, 42 and 48 | up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | Number of participants with adverse events as a measure of safety and tolerability | Study Days 1, 4, 8, 11 of 6 cycles (up to 3 weeks each) and Days 63/126, then Study Months 6, 9, 12, 15, 18, 21, 24, 30, 36, 42 and 48 | 
| Rate of progression of disease | Summary data on time to progression of disease of study subjects | Study Days 1, 4, 8, 11 of 6 cycles (up to 3 weeks each) and Days 63/126, then Study Months 6, 9, 12, 15, 18, 21, 24, 30, 36, 42 and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Follicular, Marginal Zone, Mantle Cell, Velcade, bortezomib, Nipent, pentastatin, Rituxan, rituximab, Turturro, Shreveport