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

University of Nebraska

Status and phase: Completed; Phase 1

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

Treatments: Genetic: polymorphism analysis; Drug: carboplatin; Genetic: microarray analysis; Drug: capecitabine; Other: pharmacological study; Drug: epirubicin hydrochloride

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00486356

0284-04-FB

P30CA036727 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 46 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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)

• Eastern Cooperative Oncology Group (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)

• alanine aminotransferase (ALT) & aspartate aminotransferase (AST) ≤ 2.5 times ULN

• Creatinine ≤ 1.6 mg/dL

• Left ventricular ejection fraction ≥ 50%

• Fertile patients must use effective contraception

• Recovered from prior therapy

• 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

Exclusion criteria

• No other potentially curative treatment options available (e.g., surgery, radiotherapy, chemoradiotherapy, or combination chemotherapy)
• No leukemia or lymphoma
• No primary central nervous system (CNS) malignancies or CNS metastases
• 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
• No prior doxorubicin at cumulative doses > 300 mg/m²
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent cimetidine

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

---

46 participants in 1 patient group

Capecitabine, Epirubicin, and Carboplatin

Experimental group

Description:

Determine the recommended phase II dose of capecitabine when given together with epirubicin and carboplatin in treating patients with progressive, unresectable, or metastatic cancer.

Treatment:

Other: pharmacological study

Drug: epirubicin hydrochloride

Drug: capecitabine

Genetic: microarray analysis

Drug: carboplatin

Genetic: polymorphism analysis