RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of combination chemotherapy in treating patients who have advanced solid tumors.

Condition	Treatment or Intervention	Phase
unspecified adult solid tumor, protocol specific	Procedure: chemotherapy  Procedure: enzyme inhibitor therapy  Drug: fluorouracil  Drug: leucovorin calcium  Drug: PS-341	Phase I

Further Study Details: 

OBJECTIVES: I. Determine the maximum tolerated dose and dose-limiting toxicity of PS-341 in combination with leucovorin calcium and fluorouracil in patients with advanced solid tumors. II. Determine the pharmacodynamics of PS-341, in terms of 20S proteasome and NFkB inhibition, in patients treated with this regimen. III. Determine the objective tumor response in these patients. IV. Determine the correlation between 20S proteasome and NFkB inhibition and clinical toxicity in these patients. V. Determine the pharmacokinetics of fluorouracil in combination with PS-341 in these patients.

PROTOCOL OUTLINE: This is a multicenter, dose-escalation study of PS-341. Patients receive PS-341 IV on days 1 and 4 and fluorouracil IV and leucovorin calcium IV on day 1 weekly for 4 weeks. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3 to 6 patients receive escalating doses of PS-341 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.

PROJECTED ACCRUAL: A total of 15 to 30 patients will be accrued for this study within 1 year.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically or cytologically confirmed metastatic or unresectable solid tumor not amenable to standard therapy
• No brain metastases

--Prior/Concurrent Therapy--

• Biologic therapy: At least 4 weeks since prior immunotherapy and recovered
• Chemotherapy: At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered
• Endocrine therapy: Not specified
• Radiotherapy: At least 4 weeks since prior radiotherapy and recovered
• Surgery: At least 2 weeks since prior major surgery
• Other: No other concurrent investigational agents; No concurrent antiretroviral therapy (HAART) for HIV

--Patient Characteristics--

• Age: 18 and over
• Performance status: ECOG 0-2 OR Karnofsky 60-100%
• Life expectancy: At least 3 months
• Hematopoietic: Absolute neutrophil count at least 1,500/mm3; Platelet count at least 100,000/mm3
• Hepatic: Bilirubin no greater than normal; AST/ALT no greater than 2.5 times upper limit of normal
• Renal: Creatinine no greater than 1.5 mg/dL
• Cardiovascular: No symptomatic congestive heart failure; No unstable angina pectoris; No cardiac arrhythmia; No EKG evidence of acute ischemia or significant conduction abnormality; No history of cardiac or cerebrovascular disease due to hypotension and tachycardia
• Other: No other concurrent uncontrolled illness; No ongoing or active infection; Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception

California
      Cancer Center and Beckman Research Institute, City of Hope, Duarte,  California,  91010-3000,  United States
      University of California Davis Cancer Center, Sacramento,  California,  95817,  United States
      USC/Norris Comprehensive Cancer Center and Hospital, Los Angeles,  California,  90033-0804,  United States

Study chairs or principal investigators

Heinz-Josef Lenz,  Study Chair,  Beckman Research Institute   

Study ID Numbers:  CDR0000068327; CHNMC-PHI-27; NCI-T99-0048; LAC-USC-0C003
Record last reviewed:  February 2004
Last Updated:  October 13, 2004
Record first received:  January 6, 2001
ClinicalTrials.gov Identifier:  NCT00007878
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08