OBJECTIVES:

Primary

• Determine the maximum tolerated dose of flavopiridol when administered with a fixed dose of doxorubicin in patients with unresectable metastatic or locally recurrent sarcoma.

Secondary

• Determine the clinical pharmacokinetics of this regimen in these patients.
• Determine, preliminarily, the therapeutic activity of this regimen in these patients.
• Correlate pRb, p53, and p21 protein levels with treatment response and apoptosis in patients treated with this regimen.
• Correlate NMR biochemical patterns with response in patients treated with this regimen.

OUTLINE: This is an open-label, dose-escalation study of flavopiridol.

Patients receive doxorubicin IV over 5-10 minutes and flavopiridol IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients reaching a cumulative doxorubicin dose of 600 mg/m^2 or experiencing cardiotoxicity may receive flavopiridol alone at the discretion of the investigator.

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. Ten additional patients receive treatment at the MTD.

Patients are followed every 3 months for 1 year.

PROJECTED ACCRUAL: A total of 3-36 patients will be accrued for this study within 1-2 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed soft-tissue sarcoma*

  • Unresectable disease
  • Locally recurrent or metastatic disease
• Disease amenable to biopsy (patients treated at the maximum tolerated dose only)
• No known prior or concurrent brain metastases NOTE: *Patients with gastrointestinal stromal tumors should receive therapy with imatinib mesylate first if eligible for both types of therapy

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Karnofsky 60-100% OR
• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• AST and ALT ≤ 2.5 times upper limit of normal

Renal

• Creatinine ≤ 1.5 mg/dL OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• Ejection fraction ≥ 50% by MUGA or echocardiogram
• No uncontrolled hypertension
• No myocardial infarction
• No New York Heart Association class II-IV congestive heart failure
• No unstable angina
• No serious cardiac arrhythmia requiring medication
• No peripheral vascular disease ≥ grade 2 within the past year
• No other clinically significant cardiac disease
• No prior deep vein thrombosis
• No other prior vascular thrombus

Pulmonary

• No prior pulmonary embolism

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No symptomatic peripheral neuropathy ≥ grade 2

• No other malignancy within the past 5 years except adequately treated basal cell skin cancer or carcinoma in situ of the cervix

  • Carcinoma in situ not considered a second malignancy
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to study drugs
• No psychiatric illness or social situation that would preclude study compliance
• No ongoing or active infection
• No other uncontrolled illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Chemotherapy
• At least 3 weeks since prior immunotherapy and recovered

Chemotherapy

• At least 3 weeks since prior chemotherapy (6 weeks for carmustine or mitomycin) and recovered

• No more than 2 prior cytotoxic chemotherapy regimens

  • Peroxisome proliferator-activated receptor (PPAR)-gamma agonists, thalidomide, or targeted therapy (i.e., tyrosine kinase inhibitors including imatinib mesylate, sorafenib, or sunitinib malate) do not count as a prior chemotherapy regimen
• No prior anthracyclines

Endocrine therapy

• Not specified

Radiotherapy

• At least 3 weeks since prior radiotherapy and recovered
• No prior extensive radiotherapy to bone marrow-producing sites (e.g., radiotherapy to both the pelvis and spine)

Surgery

• Not specified

Other

• At least a 1 week washout period since prior tyrosine kinase inhibitors or other targeted therapy
• Concurrent low-dose warfarin (1 mg per day) to prevent thrombus of a central line allowed
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent anticancer therapy