Fludarabine, Velcade and Rituximab for Relapsed or Refractory Follicular Non-Hodgkin Lymphoma

OUTLINE: This is a multi-center study.

- Fludarabine 25 mg/m2 IV over 30 minutes , Days 1, 2, 4

- Velcade(given after fludarabine) 1.3 mg/m2 IV push over 3 to 5 seconds, Days 1, 4, 8,
11

- Rituximab (given after Velcade) 375 mg/m2 IV piggyback, Day 1

- Cycle = 28 days; max 6 cycles

ECOG Performance Status: 0-2

Life Expectancy: Not specified

Hematopoietic:

- Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 (ANC > 0.5 K/mm3 if known lymphomatous
involvement of the bone marrow).

- Platelets ≥ 100 K/mm3 (Platelets >50 K/mm3 if known lymphomatous involvement of the
bone marrow).

Hepatic:

- Total bilirubin ≤1.5 ULN

- Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN

- Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x ULN

Renal:

- Creatinine < 1.5 x institutional upper limit (ULN) or creatinine clearance ≥ 50 cc/min

Cardiovascular:

- No myocardial infarction within 6 months prior to enrollment

- No heart failure per New York Heart Association Classification III or IV

- No severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of
acute ischemia

Inclusion Criteria:

- Must have histologically confirmed Follicular Non-Hodgkin Lymphoma (Grade I, II, or
IIIa)

- Must have measurable disease defined as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded as ≥2 cm with
conventional techniques or as >1 cm with spiral CT scan) and obtained by imaging
within 30 days prior to registration for protocol therapy.

- Must have received at least one prior therapeutic regimen, but no more than three
prior regimens of conventional cytotoxic therapy. NOTE: Prior recipients of stem cell
transplantation will be included, with the preparative cytoreductive and high-dose
therapies counted collectively as one prior therapy.

- Must be off all cytotoxic chemotherapy for at least four weeks prior to registration
for protocol therapy (6 weeks for BCNU or mitomycin C).

- Patients are allowed to have received one course of prior radioimmunotherapy (RIT:
either tositumomab or ibritumomab). NOTE: Radioimmunotherapy must be completed at
least 12 weeks prior to registration for protocol therapy with recovery to baseline
of ANC and platelets.

- Prior fludarabine, Velcade or rituximab is allowed as long as therapy is completed at
least 30 days prior to registration for protocol therapy. Patients may be refractory
(defined as not responding or demonstrating progressive disease in <6 months) to
prior rituximab. Patients may not be refractory to prior fludarabine or Velcade.

- Females of childbearing potential and males must be willing to use an effective
method of contraception (hormonal or barrier method of birth control; abstinence)
from the time consent is signed and for 30 days following protocol therapy. Should a
woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately.

- Females of childbearing potential must have a negative serum pregnancy test within 7
days prior to prior to registration for protocol therapy. NOTE: Patients are
considered of child bearing potential unless they are surgically sterile (they have
undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or
they are postmenopausal (no menses for at least 12 months).

- Females must not be breastfeeding.

- Males must agree to use an acceptable method of contraception for the duration of the
study.

Exclusion Criteria:

- No current active CNS metastases. Patients with neurological symptoms must undergo a
head CT scan or brain MRI to exclude brain metastasis within 7 days prior to
registration for protocol therapy. NOTE: Patients with treated brain metastasis must
be off steroids or on tapering or stable doses of steroids and have completed
radiation at least 30 days prior to registration for protocol therapy.

- No prior malignancy is allowed except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, Gleason ≤ grade 6 prostate cancers, or
other cancer for which the subject has been disease-free for at least 3 years.

- No treatment with any investigational agent within 30 days prior to registration for
protocol therapy.

- Prior radiation therapy is allowed to < 25% of the bone marrow. NOTE: No radiation
therapy within 30 days prior to registration for protocol therapy.

- No clinically significant infections as judged by the treating investigator.

- No active HIV, hepatitis B or hepatitic C infection.

- No cerebrovascular accident (CVA) within 6 months of study enrollment.

- No psychiatric illness/social situations that would limit compliance with study
requirements.

- No history of hypersensitivity to Velcade, boron or mannitol.

- No peripheral neuropathy grade > 1.