• Maximum tolerated dose assessed every 28 days [ Designated as safety issue: Yes ]
  

• Antitumor activity of flavopiridol as measured by CT, MRI, or positron-emission test (PET) scans at every other course [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of flavopiridol in patients with metastatic or unresectable refractory solid tumors or hematologic malignancies. (Accrual for patients with hematologic malignancies temporarily closed as of 11/30/04)

Secondary

• Determine the safety profile and toxic effects of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Determine, by pharmacodynamic assays, the ability of this drug to inhibit cyclin-dependent kinase activity in tumor tissue, normal proliferating tissues, circulating tumor cells, and in plasma in these patients.
• Determine, preliminarily, the antitumor activity of this drug in these patients.

OUTLINE: This is a 2-part, dose-escalation, multicenter study.

• Part 1 (closed to accrual as of 8/2005): Patients receive flavopiridol IV over 1 hour on days 1, 8, and 15.

Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD)* is determined.

• Part 2: Patients receive flavopiridol IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of flavopiridol IV over 1-6 hours on days 1, 8, and 15.

Cohorts of 3-6 patients receive escalating durations of the maintenance dose of flavopiridol until the MTD* is determined. An additional cohort of 10-20 patients receives flavopiridol over 1 hour on days 1 and 15 at the MTD.

NOTE: *The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

In both parts, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients are followed at 1 month and then every 2 months thereafter.

PROJECTED ACCRUAL: Approximately 3-80 patients will be accrued for this study within 1-4 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed malignancy, including the following types:

  • Hematologic malignancy, including any of the following: (Accrual for patients with hematologic malignancies temporarily closed as of 11/30/04)

    • Mantle cell lymphoma

      • Morphologically confirmed disease
      • CD20 and CD5 positive
    • Any other refractory lymphoma

    • Chronic lymphocytic leukemia

      • Rai stage III or IV and meeting at least 1 of the following criteria for active disease:

        • Weight loss > 10% in the last 6 months
        • Fatigue
        • Fever or night sweats with no evidence of infection
        • Progressive anemia or thrombocytopenia
        • Progressive lymphocytosis with a lymphocyte doubling time of < 6 months
        • Marked hypogammaglobulinemia or paraproteinemia
        • Progressive splenomegaly and/or lymphadenopathy

    • Multiple myeloma

      • Disease confirmed by bone marrow aspirate and/or biopsy
      • Relapsed or refractory disease after the most recent treatment regimen
      • Quantifiable monoclonal immunoglobulin in serum and/or urine

  • Solid tumor, including but not limited to any of the following:

    • Breast cancer

      • Histologically or cytologically confirmed stage IV invasive disease

      • HER-2 positivity not required for study enrollment

        • Tumor overexpressing HER-2 should be confirmed by immunohistochemistry OR fluorescence in situ hybridization

    • Small cell lung cancer

      • Extensive stage or limited stage disease in relapse
      • Extrapulmonary small cell carcinoma allowed

    • Squamous cell carcinoma of the head and neck

      • Metastatic, recurrent, or refractory disease
    • Renal cell carcinoma

    • Mesothelioma

      • Pleural or peritoneal disease of epithelial, sarcomatoid, or mixed subtype
    • Melanoma
    • Kaposi's sarcoma
• Metastatic or unresectable disease for which standard therapy does not exist or is no longer effective

• Measurable or nonmeasurable disease (solid tumor patients)

  • Measurable disease defined as at least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or 10 mm by spiral CT scan

  • Nonmeasurable disease includes any of the following:

    • All other lesions, including lesions < 20 mm by conventional techniques or 10 mm by spiral CT scan
    • Bone lesions
    • Cytologically positive pleural or peritoneal disease
    • Elevated tumor marker (e.g., CEA, CA 125, CA 19-9, or other tumor marker)
    • Multinodular or confluent nonmeasurable pulmonary, hepatic, adrenal, intra-abdominal, or skin metastases

• Previously treated with at least 1 chemotherapy regimen*

  • Prior therapy may have included combined modality treatment (e.g., full-dose chemotherapy and radiotherapy with radiosensitizing chemotherapy)
  • Prior therapy with flavopiridol allowed provided the patient was enrolled in a flavopiridol clinical trial employing a different schedule NOTE: *Except in cases where chemotherapy is not known to be effective (e.g., renal cell carcinoma, chondrosarcoma, or gastrointestinal stromal tumor)

• No active CNS metastases

  • History of CNS metastases allowed provided all of the following criteria are met:

    • Previously treated and stable and asymptomatic for at least 4 weeks since the completion of treatment
    • Image documentation required
    • Off steroids or on a stable dose of steroids for at least 1 week

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Male or female

Menopausal status

• Not specified

Performance status

• ECOG 0-1 OR
• Karnofsky 70-100%

Life expectancy

• More than 12 weeks

Hematopoietic

• Absolute neutrophil count > 1,000/mm^3*
• Platelet count > 75,000/mm^3 (50,000 for hematologic malignancies)* (Accrual for patients with hematologic malignancies temporarily closed as of 11/30/04) NOTE: *Unless abnormality is caused by tumor burden and not cumulative prior chemotherapy

Hepatic

• Bilirubin normal
• AST/ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)

Renal

• Creatinine ≤ 2.0 mg/dL OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• No myocardial infarction within the past 6 months
• No unstable angina within the past 6 months
• No transient ischemic attack or cerebrovascular accident within the past 6 months
• No history of arterial vascular events
• No new cardiac arrhythmias likely to be related to cardiac ischemia within the past 6 months
• No symptomatic congestive heart failure

Pulmonary

• No history of pulmonary embolism within the past 6 months

Gastrointestinal

• No chronic diarrheal disease within the past 6 months
• No severe malnutrition
• No intractable emesis

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective hormonal or barrier contraception
• No ongoing or active infection
• No other concurrent uncontrolled illness
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior biologic therapy (e.g., monoclonal antibody therapy, immunologic therapies, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, or other investigational agents) allowed
• At least 4 weeks since prior monoclonal antibody therapy

Chemotherapy

• See Disease Characteristics
• At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics
• At least 3 weeks since prior radiotherapy
• No prior radiotherapy to 50% or more of bone marrow

Surgery

• Not specified

Other

• Recovered from all prior therapy
• No other concurrent investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients