Phase I/II Trial of VELCADE Plus Zevalin in Patients With Relapsed or Refractory Follicular Lymphoma

A Phase I/II Trial of Combined Weekly Bortezomib (VELCADE®) and Y-90-Ibritumomab Tiuxetan (Zevalin) in Patients With Relapsed or Refractory Follicular Lymphoma and Transformed Non-Hodgkin's Lymphoma

Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving bortezomib together with rituximab and yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells. This phase I/II trial is studying the side effects and best dose of bortezomib when given together with rituximab and yttrium Y 90 ibritumomab tiuxetan and to see how well they work in treating patients with relapsed or refractory follicular non-Hodgkin's lymphoma.

This is a phase I, dose-escalation study of bortezomib followed by a phase II study. Phase I: - Induction therapy: Patients receive bortezomib IV over 3-5 seconds on days 1, 8, 15, and 22, rituximab IV on days 8 and 15, and yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 15. Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. - Consolidation therapy: Beginning 6-7 weeks after completing induction therapy, patients receive bortezomib IV over 3-5 seconds on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Phase II: Patients receive induction therapy and consolidation therapy as in phase I, with bortezomib administered at the MTD determined in phase I. After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter. A total of 24 patients will be accrued for this study.

Induction therapy will last 28 days. Bortezomib will be given on days 1, 8, 15, and 22. Rituximab will be given on days 8 and 15 along with 111-indium-ibritumomab tiuxetan. During consolidation therapy, Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle for a maximum of 3 cycles. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.

Induction therapy will last 28 days. Bortezomib will be given on days 1, 8, 15, and 22. Rituximab will be given on days 8 and 15 along with 111-indium-ibritumomab tiuxetan. During consolidation therapy, Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle for a maximum of 3 cycles. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.

Induction therapy will last 28 days. Bortezomib will be given on days 1, 8, 15, and 22. Rituximab will be given on days 8 and 15 along with 111-indium-ibritumomab tiuxetan. During consolidation therapy, Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle for a maximum of 3 cycles. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.

Induction therapy will last 28 days. Bortezomib will be given on days 1, 8, 15, and 22. Rituximab will be given on days 8 and 15 along with 111-indium-ibritumomab tiuxetan. During consolidation therapy, Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle for a maximum of 3 cycles. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.

Maximum Tolerated Dose (MTD) and Tolerability of Bortezomib Combined With Y-90-Ibritumomab Tiuxetan Determined by Number of Dose Limiting Toxicities in a Cohort.

To determine the MTD using a 3+3 dose escalating design. There will be 3 dose cohorts:1.0mg/m2,1.3mg/m2 and1.6 mg/m2. 3 patients will be enrolled at dose of 1.0mg/m2 bortezomib. If no dose limiting toxicities (DLTs) are seen in the first 3 patients then dose will be escalated to next level and 3 patients will be treated at that dose level. If a DLT is seen at any dose, then 3 more patients will be enrolled at that dose level. If 1 patient out of 6, experience a DLT then MTD will be determined to be at this dose level. If 2 or more DLTs are seen in first 3 patients at that dose, then MTD will be one dose lower to the level where the DLTs were experienced. DLTs were defined using the National Cancer Institute Common Toxicity Criteria Version 3.0. DLTs=grade 3 nausea, vomiting, diarrhea or ileus more than 96h; grade 4 nausea, vomiting, diarrhea or ileus,neuropathic pain, peripheral sensory neuropathy, neutropenia, thrombocytopenia.

Number of Patients With Adverse Events Related to Treatment of Bortezomib Combined With Y-90-ibritumomab Tiuxetan

To further explore the toxicity bortezomib combined with Y-90-ibritumomab tiuxetan by collecting data on adverse events (AE) reported by patient or collected lab results that are grade 3 or grade 4 that were determined to be at least possible related to any of the studies drugs. Toxicity will be collected on treatment days according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

At start of treatment on days 1, 8, 15, 22 of induction, days 36 and 50 of recovery, days 1, 8, 15 of consolidation cycles for up to 3 cycles and 4 weeks after the completion of treatment.

Inclusion Criteria: Histologically confirmed follicular lymphoma CD20+ at time of diagnosis or subsequently More than 4 weeks since prior rituximab More than 3 weeks since prior anticancer therapy (6 weeks for nitrosourea or mitomycin C) More than 4 weeks since prior major surgery More than 2 weeks since prior investigational drugs Exclusion Criteria: AIDS-related lymphoma History or evidence of CNS involvement Pregnant or nursing known HIV positivity serious medical or psychiatric illness that would preclude study participation myocardial infarction within the past 6 months congestive heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia or active conduction system abnormalities known hypersensitivity to rituximab, bortezomib, boron, or mannitol prior autologous or allogeneic stem cell transplantation prior radioimmunoconjugate therapy or prior exposure to murine antibodies prior external-beam irradiation to > 25% of active bone marrow