Study of Standard-Dose Rituximab, Ifosfamide, Carboplatin and Etoposide

Once subjects are determined to be eligible and informed consent is obtained,patients will be enrolled into a starting dose cohort of 1.0mg/m2. Based upon a satisfactory safety profile, additional patients will be enrolled into the 1.3, 1.5 and 1.7mg/m2 cohorts. Each of these dosing cohorts will only be enrolled if satisfactory safety profiles in each of the lower dosing cohorts are obtained. As the process continues, multiple cohorts will be receiving various dosing regimens simultaneously. If a DLT occurs in ≥2 out of 6 patients at the initial dose level, then 3 more patients will be accrued at dose level -1 (0.7mg/m2). Bortezomib will be given on days 1 (prior to rituximab) and 4, rituximab 375 mg/m2 on day 1, carboplatin AUC 5 and ifosfamide with mesna, each 5 gm/m2, on day 3 and etoposide 100 mg/ m2/day on days 2, 3 and 4 of a 21-day cycle. They will also receive filgrastim on days 6-13 or pegfilgrastim on day 6. Dose-limiting toxicities (DLT) include any grade 3 or 4 non-hematologic toxicities (except alopecia and grade 3 febrile neutropenia), grade 4 febrile neutropenia (life-threatening sepsis) and grade 4 neutropenia persisting past day 35 or grade 3 or 4 thrombocytopenia persisting past day 35. If there is a DLT at a given bortezomib dose level, 3 more subjects will be enrolled at that dose; if there are 2 or more DLTs then the MTD will be defined as the previous dose level. If at that dose level, \>50% of subjects required bortezomib dose reduction, the MTD will be defined as the next lower dose level. Subjects will continue to be accrued in order to treat a minimum of 10 patients at the MTD. Those who are candidates for autologous stem cell transplant will have CT scan of the neck, chest, abdomen and pelvis after 2 cycles. Subjects with PD or SD will be taken off study. Those with CR, PR or response not meeting PR criteria will undergo a total of 3 cycles of bortezomib + RICE. After the 3rd cycle of bortezomib + RICE, whole body PET/CT scan and bone marrow biopsy will be obtained. Subjects who achieve CR or PR will then proceed to stem cell mobilization and collection by a standard regimen, followed by autologous stem cell transplant with a preparative regimen to be determined by the investigator. Those with SD or PD will be taken off study. While the mobilization and ASCT procedures are not part of the phase I protocol, outcomes of ASCT will be followed, including CD34+ progenitor cell collection, clinical response to transplant and survival. Subjects who are not candidates for autologous stem cell transplant will have CT scan of the neck, chest, abdomen and pelvis after the 2nd and 4th cycles. Those who are responding will continue for a maximum of 6 cycles.