A Phase I Clinical, Pharmacokinetic and Pharmacodynamic Study of Flavopiridol in Patients With Refractory Solid Tumors and Hematologic Malignancies
Inclusion Criteria:
- 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
- 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
- At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
- At least 3 weeks since prior radiotherapy No prior radiotherapy to 50% or more of
bone marrow
- Recovered from all prior therapy No other concurrent investigational agents No
concurrent combination antiretroviral therapy for HIV-positive patients
