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.

Inclusion Criteria:

- Aggressive B-cell non-Hodgkin lymphoma, CD-20 positive, in first relapse or
refractory to first- or second-line chemotherapy (non-platinum)

- Diffuse large B-cell Lymphoma, Mantle Cell Lymphoma, Follicular Lymphoma (Grade
III), Transformed Follicular Lymphoma

- Prior Rituximab is allowed

- Prior radiation is allowed

- Prior autologous stem cell transplant is allowed

- Age 18-70 years

- ECOG performance status 0-2

- HIV seronegative

- No CNS involvement: CSF cytology is required for cases with bone marrow involvement,
involvement of 2 or more extranodal sites, presentation in the testes or paranasal
sinuses, or if any clinical suspicion of CNS involvement (e.g., cranial nerve
deficits)

- Measurable disease on CT scan by international working group response criteria •
Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

- Female subject is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study.

- Male subject agrees to use an acceptable method for contraception for the duration of
the study.

Exclusion Criteria:

- Subject has a platelet count of less than 75,000.

- Subject has an absolute neutrophil count of less than 1000

- Subject has a calculated or measured creatinine clearance of <60 mL/minute within 14
days before enrollment.

- Subject has grade 2 or greater peripheral neuropathy or grade 1 with pain within 14
days before enrollment.

- Myocardial infarction within 6 months prior to enrollment or has New York Hospital
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Prior to study entry, any ECG
abnormality at Screening has to be documented by the investigator as not medically
relevant.

- Subject has hypersensitivity to bortezomib, boron or mannitol.

- Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum pregnancy test result obtained
during screening. Pregnancy testing is not required for post-menopausal or
surgically sterilized women.

- Subject has been treated with more than two prior chemotherapy regimens

- Subject has been treated with a platinum-based regimen.

- Subject has received other investigational drugs with 14 days before enrollment

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.