Capecitabine, Epirubicin, and Carboplatin in Treating Patients With Progressive, Unresectable, or Metastatic Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as capecitabine, epirubicin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of capecitabine when given together with epirubicin and carboplatin in treating patients with progressive, unresectable, or metastatic cancer.

Detailed Description
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OBJECTIVES: Primary Determine the recommended phase II dose of capecitabine when given together with epirubicin hydrochloride and carboplatin in patients with progressive, unresectable, or metastatic cancer. Determine the toxicities of this regimen in these patients. Secondary Correlate end-of-infusion levels of epirubicin hydrochloride and its metabolites with epirubicin hydrochloride dose and clinical toxicity in these patients. Correlate the pharmacokinetics of capecitabine with clinical toxicity in these patients. Determine the possible correlation between polymorphisms in the promoter region of the thymidylate synthase gene with clinical toxicity in these patients. Document antitumor activity of this regimen in these patients. OUTLINE: This is a dose-escalation study of capecitabine. Patients receive epirubicin hydrochloride IV over 2 hours and carboplatin IV over 30 minutes on day 1 and oral capecitabine twice daily on days 2-5, 8-12, and 15-19. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of capecitabine 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. Peripheral blood is collected for pharmacokinetic and pharmacogenetic studies before beginning study treatment and periodically during study. Samples for the pharmacogenetic studies are analyzed for correlation between polymorphisms in the promoter region of the thymidylate synthase gene and clinical toxicity. Patients also undergo bone marrow aspirate before beginning study treatment for molecular profiling studies.

Official Title
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A Phase I Trial of Epirubicin, Carboplatin and Capecitabine in Adult Cancer Patients

Conditions
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Extrahepatic Bile Duct Cancer, Gallbladder Cancer, Gastric Cancer, Liver Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: capecitabine
* Drug: carboplatin
* Drug: epirubicin hydrochloride
* Genetic: microarray analysis
* Genetic: polymorphism analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Pathologically confirmed cancer, meeting 1 of the following criteria: Disease that has progressed on standard therapy Locally advanced but unresectable primary or recurrent solid tumor Metastatic disease, including previously untreated metastatic disease for which study regimen represents reasonable initial chemotherapy with palliative intent (e.g., metastatic gastric cancer, hepatobiliary cancer, or cancer for which no effective standard therapy exists) No other potentially curative treatment options available (e.g., surgery, radiotherapy, chemoradiotherapy, or combination chemotherapy) No leukemia or lymphoma No primary CNS malignancies or CNS metastases PATIENT CHARACTERISTICS: ECOG performance status 0-2 Absolute neutrophil count ≥ 2,000/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Creatinine ≤ 1.6 mg/dL Left ventricular ejection fraction ≥ 50% No other medical illness that would preclude study treatment No active infection requiring IV antibiotic therapy unless the infection has resolved No history of allergy to platinum compounds, mannitol, or to antiemetics appropriate for administration in conjunction with protocol-directed chemotherapy No history of unexpectedly severe intolerance to fluorouracil Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior therapy No prior doxorubicin at cumulative doses > 300 mg/m² More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) or immunotherapy At least 2 weeks since prior radiotherapy At least 8 weeks since prior strontium therapy At least 4 weeks since prior and no concurrent sorivudine or brivudine No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent cimetidine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capecitabine, Epirubicin, and Carboplatin<br> | Drug: capecitabine<br> <br> Drug: carboplatin<br> <br> Drug: epirubicin hydrochloride<br> <br> Genetic: microarray analysis<br> <br> Genetic: polymorphism analysis<br> <br> Other: pharmacological study<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose of capecitabine |  | Every 28-days until progression. | 
| Toxicities |  | Every 28-days until progression. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of end-of-infusion levels of epirubicin hydrochloride and its metabolites with epirubicin hydrochloride dosing and clinical toxicity |  | Each day of dosing | 
| Correlation of the pharmacokinetics of capecitabine with clinical toxicity |  | Each day of dosing | 
| Possible correlation between polymorphisms in the promoter region of the thymidylate synthase gene with clinical toxicity |  | Post-treatment | 
| Antitumor activity |  | Prior to cycle 1 and then every 2 cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific, recurrent gastric cancer, stage IV gastric cancer, advanced adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer, recurrent extrahepatic bile duct cancer, unresectable extrahepatic bile duct cancer, recurrent gallbladder cancer, unresectable gallbladder cancer