Combination Chemotherapy With or Without Bortezomib in Treating Patients With Classical Hodgkin Lymphoma That Has Returned or Does Not Respond to Prior Treatment.

PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR), partial remissions (PR), and complete
remissions (CR) after 3 cycles of bortezomib plus ifosfamide, carboplatin, and etoposide
(ICE) (BICE) versus ICE in patients with relapsed/refractory classical Hodgkin lymphoma
(cHL).

II. To evaluate 2-year progression-free survival (PFS) in patients treated with 3 cycles of
BICE versus ICE.

SECONDARY OBJECTIVES:

I. To compare positron emission tomography (PET) scan response after 3 cycles of BICE versus
ICE chemotherapy.

II. To compare serum levels of tumor necrosis factor (TNF) proteins (a proliferation-inducing
ligand [APRIL], B lymphocyte stimulator [BLyS], soluble [s]CD30, and CD40L) and CC thymus and
activation-related cytokine (TARC) at baseline and after 3 cycles of BICE versus ICE
chemotherapy.

III. To correlate baseline cytokine/chemokine levels with response to therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive bortezomib intravenously (IV) over 5 seconds on days 1 and 4,
ifosfamide IV continuously over 24 hours on day 1, carboplatin IV over 1 hour on day 1, and
etoposide IV over 2 hours on days 1-3. Treatment repeats every 14 days for up to 6 courses in
the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive ifosfamide, carboplatin and etoposide as in Arm A. Treatment repeats
every 14 days for up to 6 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 4 months for 2 years.

Inclusion Criteria:

- Relapsed or refractory classical Hodgkin lymphoma.

- Patients must have received a front-line standard anthracycline-containing regimen,
such as adriamycin-bleomycin-vinblastine-dacarbazine (ABVD), Stanford V, or
bleomycin-etoposide-adriamycin-cyclophosphamide-oncovin-procarbazine-prednisone
(BEACOPP).

- Bi-dimensionally measurable disease with at least 1 lesion >= 2.0 cm in a single
dimension.

- Absolute neutrophil count (ANC) >= 1,500/microL.

- Platelet count >= 100,000/ microL.

- Hemoglobin >= 8 g/dL.

- Serum bilirubin < 2.0 mg/dL.

- Alkaline phosphatase < 2 x upper limits of normal (ULN).

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 x ULN.

- Serum creatinine =< 1.5 mg/dL.

- Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to
2.

- Females of childbearing potential must have a negative serum beta-human chorionic
gonadotropin (hCG) pregnancy test and must agree to use 2 highly effective
contraceptive methods (hormonal contraceptive, intra-uterine device, diaphragm with
spermicide, condom with spermicide, or abstinence) during the study and for 3 months
after completion of protocol treatment. Females of non-childbearing potential are
those who are postmenopausal for greater than 1 year or whom have had a bilateral
tubal ligation or hysterectomy.

- Males who have partners of childbearing potential must agree to use an effective
contraceptive method during the study and for 3 months after completion of protocol
treatment.

- 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.

Exclusion Criteria:

- Lymphocyte predominant Hodgkin lymphoma histology.

- More than one prior chemotherapy regimen.

- Prior autologous or allogeneic stem cell transplant.

- Presence of central nervous system (CNS) involvement with Hodgkin lymphoma.

- Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency
syndrome (AIDS).

- Active hepatitis B or C infection or history of cirrhosis.

- Grade 2 or greater peripheral neuropathy within 14 days of enrollment.

- Hypersensitivity to boron or mannitol.

- Prior bortezomib therapy.

- Another primary malignancy (other than squamous cell and basal cell carcinoma of the
skin, in situ carcinoma of the cervix, or squamous intraepithelial lesion on PAP
smear, or treated prostate cancer with a stable prostate specific antigen [PSA]) for
which the patient has not been disease-free for at least 3 years.

- Patients with congestive heart failure, Class III or IV, by New York Heart Association
(NYHA) criteria.

- Patients with a myocardial infarction 6 months prior to enrollment, uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiogram (ECG)
evidence of acute ischemia or active conduction system abnormalities.

- Patient with other medical or psychiatric illness that is likely to interfere with
participation in this clinical study.

- Female subject that is pregnant or breast-feeding.

- Patient that has received other investigational drugs within 14 days of enrollment.

- Patients using concurrent therapy with corticosteroids at greater than or equal to 20
mg/day of prednisone equivalent.

- Patients with active systemic bacterial, viral, or fungal infections that have
required IV antimicrobials within 4 weeks prior to protocol treatment.