Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

PRIMARY OBJECTIVES:

I. Determine the disease-specific dose-limiting toxicity and maximum tolerated dose of
flavopiridol in patients with relapsed or refractory lymphoma or multiple myeloma.

II. Determine the complete and partial response rate in patients with selected non-Hodgkin's
lymphoma (e.g., indolent B-cell, mantle cell, intermediate grade B-cell, and T/NK-cell),
Hodgkin's lymphoma, or multiple myeloma treated with this drug.

III. Determine the qualitative and quantitative toxic effects or this drug, in terms of
organ specificity, time course, predictability, and reversibility in these patients.

IV. Determine subsets of lymphoid/plasma cell malignancies that are suitable for larger
phase II studies designed to further evaluate the efficacy and toxicity of this drug in
these patients.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of this drug in these patients. II. Determine the effect
of this drug on innate immunity (including T-, B-, and NK-cell subsets) and quantitative
immunoglobulin levels in these patients.

III. Determine whether acute infusion toxicity (e.g., fever, hypotension, tumor pain, and
dyspnea) observed with other flavopiridol treatment schedules is related to a
cytokine-release syndrome in these patients.

IV. Determine whether this drug induces response (independent of p53 mutational status) in
these patients.

OUTLINE: This is a phase I, dose-escalation study followed by a multicenter, phase II, pilot
study. Patients enrolled in the phase II portion of the study are stratified according to
diagnosis.

PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment
repeats every 6 weeks for up to 6 courses in the absence of disease progression or
unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of flavopiridol
until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive flavopiridol* as in phase I at the MTD determined in phase I.

NOTE: The phase II treatment dose and schedule for hairy cell leukemia patients will be
adapted from that developed in previous phase II studies of flavopiridol for the treatment
of chronic lymphocytic leukemia.

After completion of study therapy, patients are followed every 3 months for 2 years.

Inclusion Criteria:

- Diagnosis of 1 of the following hematologic malignancies:

- Hodgkin's lymphoma

- Non-Hodgkin's lymphoma (NHL)

- Multiple myeloma

- Patients in the phase II portion of the study are enrolled in 1 of the following
strata according to diagnosis*

- Stratum 1: Indolent B-cell NHL, follicle center B-cell NHL (grade 1, 2, or 3),
marginal zone lymphoma, Waldenstrom's macroglobulinemia, or small lymphocytic
lymphoma (without blood lymphocytosis at any point in the disease process)

- Must have progressive lymphadenopathy, worsening cytopenias, or progressive
symptoms attributed to lymphoma

- Must require therapy, as determined by progressive anemia,
thrombocytopenia, symptoms (e.g., fever, night sweats, weight loss, or
fatigue), or progressive lymphadenopathy that causes discomfort

- Received ≥ 2 prior therapies, including rituximab

- Stratum 1a: Hairy cell leukemia

- Must require therapy, as determined by progressive cytopenias or symptoms
(fever, night sweats, weight loss, or fatigue)

- Must have received ≥ 2 therapies

- Stratum 2: Mantle cell lymphoma, as determined by the presence of cyclin D1
staining OR t(11;14)

- Stratum 3: Intermediate grade B-cell NHL, including diffuse large B-cell NHL and
T-cell rich B-cell NHL

- Diffuse large B-cell NHL arising from an indolent NHL (i.e., transformed
lymphoma) allowed

- Ineligible for potentially curative autologous stem cell transplantation

- Stratum 4: T-cell and natural killer-cell NHL, including anaplastic large cell
lymphoma and peripheral T-cell NHL

- Primary cutaneous lymphoma or Sezary syndrome allowed provided criteria for
measurable disease are met

- Received ≥ 1 prior systemic therapy

- Stratum 5: Hodgkin's lymphoma

- Any of the following subtypes are allowed:

- Nodular sclerosing

- Mixed cellularity

- Lymphocyte predominant

- Lymphocyte depleted

- Ineligible for potentially curative autologous stem cell transplantation

- Stratum 6: Progressive stage I or stage II or IIIA multiple myeloma meeting ≥ 1
major and 1 minor criterion OR ≥ 3 minor criteria as follows:

- Major criteria

- Plasmacytoma on tissue biopsy

- Bone marrow plasmacytosis ≥ 30% of marrow cellularity

- Monoclonal paraprotein ≥ 3,500 mg/dL (IgG), or ≥ 2,000 mg/dL (IgA),
OR monoclonal protein (Bence-Jones protein) ≥ 1,000 mg by 24-hour
urine collection

- Minor criteria

- Bone marrow plasmacytosis 10-29% of marrow cellularity

- Monoclonal paraprotein < 3,500 mg/dL (IgG) or < 2,000 mg/dL (IgA)

- Lytic bone lesions by x-ray or CT scan

- Decrease in normal IgM (< 50 mg/dL), IgA (< 100 mg/dL), or IgG (< 600
mg/dL)

- Relapsed or refractory disease

- Measurable disease, defined by 1 of the following:

- At least 1 node > 2 cm by CT scan

- Measurable disease in a lymphoid structure (i.e., spleen) by CT scan

- Bone marrow involvement (> 20% of marrow cellularity)

- Patients with multiple myeloma must have detectable serum or urinary paraprotein

- Patients with only cutaneous or subcutaneous disease (i.e., no measurable lymph
node or bone marrow disease) are eligible if the extent of rash or skin
involvement OR the size of the nodules are measurable

- Must have received ≥ 1 prior therapy

- Steroids alone are not considered prior therapy for patients with NHL or
Hodgkin's lymphoma

- High-dose dexamethasone is considered 1 prior therapy for patients with multiple
myeloma

- No standard effective therapy exists

- No HIV-associated lymphoma

- No nonsecretory multiple myeloma

- Performance status - ECOG 0-2

- No concurrent hormonal therapy except steroids for new adrenal failure or hormones
administered for non-disease-related conditions (e.g., insulin for diabetes)

- Hemoglobin ≥ 9.0 g/dL*

- Absolute neutrophil count ≥ 1,500/mm^3*

- Platelet count ≥ 50,000/mm^3*

- AST ≤ 3 times upper limit of normal (ULN)

- Bilirubin ≤ 2 times ULN

- No major renal dysfunction that would preclude study compliance or participation

- Phase I:

- Creatinine ≤ 1.5 mg/dL

- Creatinine clearance ≥ 70 mL/min

- Phase II:

- Creatinine ≤ 2.0 mg/dL

- Creatinine clearance ≥ 50 mL/min

- No cardiac or vascular dysfunction that would preclude central venous access,
vigorous hydration, or hemodialysis

- No other major cardiac dysfunction that would preclude study compliance or
participation

- No major pulmonary dysfunction that would preclude study compliance or participation

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No chronic gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or
short gut syndrome) that would preclude study compliance or participation

- No other major organ system (including neurological or psychiatric) dysfunction that
would preclude study compliance or participation

- Prior radiotherapy, including radioimmunotherapy, allowed

- No concurrent radiotherapy

- Prior idiotype vaccination or stem cell transplantation allowed

- More than 6 weeks since prior mitomycin or nitrosoureas

- No other concurrent chemotherapy

- More than 4 weeks since other prior therapy

- Prior systemic steroids allowed