Imatinib, Capecitabine, and Cisplatin in Treating Patients With Unresectable or Metastatic Stomach Cancer

OBJECTIVES:

Primary

• To determine the maximum tolerable dose and assess the safety and tolerability of imatinib mesylate in combination with capecitabine and cisplatin in patients with unresectable or metastatic gastric cancer.

Secondary

• To assess the preliminary antitumor activity of this regimen in these patients.
• To assess the response with regard to the expression and/or mutation of the tyrosine kinase receptors PDGF-R and c-kit in gastric cancer.

OUTLINE: This is a dose-escalation study of imatinib mesylate.

Patients receive oral imatinib mesylate once daily on days -4 to 21 in course 1 and on days 1-21 in all subsequent courses, oral capecitabine twice daily on days 1-14, and cisplatin IV on day 1. Courses repeat every 3 weeks* for 12 months in the absence of disease progression or unacceptable toxicity.

NOTE: *First course is 25 days.

After completion of study therapy, patients are followed every 3 weeks.

DISEASE CHARACTERISTICS:

• Histologically confirmed gastric cancer

• Unresectable and/or metastatic disease
• Incurable with any conventional multimodality approach by interdisciplinary assessment of the local tumor board
• Immunohistochemical documentation of c-kit (CD117) and PDGF-R overexpression by tumor if obtainable (preferably on a tumor sample taken within 6 weeks of study entry)
• At least one evaluable site of disease according to RECIST criteria
• No known brain metastasis or CNS disorder that might alter study compliance or may worsen during or following therapy

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• WBC ≥ 3,000/μL
• ANC ≥ 2,000/μL
• Platelet count ≥ 100,000/μL
• Hemoglobin ≥ 9.0 g/dL
• Total bilirubin < 2 times upper limit of normal (ULN)
• SGOT and SGPT < 2.5 times ULN (5 times ULN if hepatic metastases present)
• Glomerular filtration rate ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for up to 3 months after completion of study treatment
• No known or documented hypersensitivity against fluoropyrimidines, tyrosine kinase inhibitors, cisplatin, other platinums, or their respective derivatives
• No gastrointestinal disorder that might affect the gastrointestinal absorption of capecitabine or imatinib mesylate or ability to swallow for the oral administration of capecitabine or imatinib mesylate
• At least 5 years since prior primary malignancy except if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or carcinoma in situ of the cervix
• No other concurrent malignant disease
• No NYHA class III-IV cardiac disease (i.e., congestive heart failure or myocardial infarction within the past 6 months)
• No severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection)
• No known neuropathy, impaired hearing, history of seizures, and/or psychiatric disorder that might alter study compliance or may worsen during or following therapy
• No documented dihydropyrimidine dehydrogenase deficiency
• No known chronic liver disease (i.e., chronic active hepatitis or cirrhosis)
• No known diagnosis of HIV infection or other serious uncontrolled infections
• No significant history of non-compliance to medical regimens or inability to grant reliable informed consent

PRIOR CONCURRENT THERAPY:

• No chemotherapy or investigational agents within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C) unless the disease is rapidly progressing
• No prior radiotherapy to ≥ 25% of the bone marrow
• No major surgery within the past 2 weeks
• No concurrent warfarin or acetaminophen

• Therapeutic anticoagulation using heparin or low-molecular weight heparin allowed
• No concurrent sorivudine or related substances
• No other concurrent anticancer agents, including chemotherapy and biologic agents
• No other concurrent investigational drugs