Clinical trial NCT00486356: Capecitabine, Epirubicin, and Carboplatin in Treating Patients With Progressive, Unresectable, or Metastatic Cancer
Official title: A Phase I Trial of Epirubicin, Carboplatin and Capecitabine in Adult Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Extrahepatic Bile Duct Cancer
Gallbladder Cancer
Gastric Cancer
Liver Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-06-14
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Recommended phase II dose of capecitabine
timeFrame: Every 28-days until first documented progression up to 63 months
measure: Toxicities of combined chemotherapy regimen
timeFrame: Every 28-days until first documented progression up to 63 months
Secondary outcomes:
measure: End-of-infusion levels of epirubicin hydrochloride/metabolites and incidence of correlation with epirubicin hydrochloride dosing and clinical toxicity
timeFrame: Each day of dosing up to 63 months
measure: Correlation of the pharmacokinetics (speed of appearance in the blood plasma and its concentration) of capecitabine with clinical toxicity
timeFrame: Each day of dosing up to 63 months
measure: Incidence of Correlation between polymorphisms in the promoter region of the thymidylate synthase gene with clinical toxicity
timeFrame: Post-treatment up to 63 months
measure: Antitumor activity
timeFrame: Prior to cycle 1, and then every two 28 day cycles up to 63 months
Other outcomes:
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center, Eppley Cancer Center
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Jean L Grem, MD
role: PRINCIPAL_INVESTIGATOR
References: