Imatinib Mesylate, Gemcitabine, and Capecitabine in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of gemcitabine hydrochloride and capecitabine when combined with imatinib mesylate in patients with advanced solid tumors.
• Determine the toxicity of this regimen in these patients.

Secondary

• Explore the antitumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study of gemcitabine and capecitabine.

Patients receive oral imatinib mesylate once daily on days 1-5 and 8-12, gemcitabine hydrochloride IV on days 3 and 10, and oral capecitabine twice daily on days 1-14. Treatment repeats every 21 days for at least 2 courses in the absence of progressive disease or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of gemcitabine hydrochloride and 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.

Existing paraffin-embedded tissue blocks from patients diagnosed with melanoma or renal cell carcinoma will be assessed for c-kit mutations by polymerase chain reaction and direct sequencing of both juxtamembrane domains (exons 9 and 11) and tyrosine kinase domain (exon 13 and 17). (Begins 12-11-2008)

PROJECTED ACCRUAL: Closed to patient accrual 12/11/2008.

Inclusion criteria

• Histologically confirmed solid tumor, meeting 1 of the following criteria:

• Failed standard therapy and subsequent line therapy
• Disease for which no standard therapy exists
• Any number of prior therapies are allowed provided standard treatment options have either been exhausted or are unable to be administered, in the opinion of the treating physician
• Measurable or nonmeasurable disease

• Measurable disease is defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by CT scan or ≥ 10 mm by spiral CT scan
• Nonmeasurable disease is defined as all other lesions, including small lesions (< 20 mm by conventional techniques or < 10 mm by spiral CT scan) and truly nonmeasurable lesions, including the following:

• Leptomeningeal disease
• Bone lesions
• Ascites
• Pleural or pericardial effusion
• Lymphangitis cutis/pulmonis
• Abdominal masses that are not confirmed and followed by imaging techniques
• Cystic lesions
• Brain metastases allowed provided both of the following are true:

• Patient has undergone resection and/or radiotherapy and does not require steroids
• No evidence of disease progression by CT scan or MRI at least 4 weeks after completion of steroids, surgery, and/or radiotherapy
• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8.5 g/dL (epoetin alfa supplementation allowed)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN) (except if due to Gilbert's syndrome)
• AST and ALT ≤ 2.5 times ULN
• Creatinine < 1.5 times ULN
• Fertile patients must use effective barrier method contraception during and for 3 months after completion of study treatment
• Must be able to tolerate oral intake for the administration of imatinib mesylate and capecitabine
• Prior treatment with gemcitabine hydrochloride, capecitabine, or imatinib mesylate allowed provided all three drugs were not used in combination simultaneously
• Prior radiotherapy allowed provided the lesion treated is not used to assess response and has not demonstrated progression after treatment
• At least 2 weeks since prior radiotherapy
• More than 2 weeks since prior major surgery
• At least 4 weeks since prior systemic therapy (6 weeks for nitrosoureas) and recovered
• More than 4 weeks since prior packed red blood cell transfusions
• Concurrent bisphosphonate therapy allowed for skeletal metastases provided therapy is started before study entry

Exclusion criteria

• Not pregnant or nursing/negative pregnancy test
• No active serious infections
• No known allergy or hypersensitivity to study drugs or their formulation
• No comorbidity or condition which would preclude study participation
• No other primary malignancy within the past 5 years except basal cell skin cancer, cervical carcinoma in situ, or another primary malignancy that is not currently clinically significant or requires active intervention
• No prior radiotherapy to ≥ 25% of the bone marrow
• No concurrent anticoagulation therapy with warfarin

• Therapeutic anticoagulation with low-molecular weight heparin or heparin allowed
• Mini-dose warfarin (e.g., 1 mg/day) for prophylaxis of central venous catheter thrombosis allowed at the discretion of the treating physician
• No other concurrent anticancer agents, including chemotherapy and biologic agents
• No other concurrent investigational drugs
• No concurrent routine systemic corticosteroid therapy (corticosteroid therapy may only be administered after consultation with the principal investigator)
• No other malignant disease
• No New York Heart Association class III-IV cardiac disease
• No congestive heart failure
• No myocardial infarction within the past 6 months
• No known chronic liver disease (e.g., chronic active hepatitis or cirrhosis)
• No known HIV infection
• No prior radiotherapy to ≥ 25% of the bone marrow
• No concurrent anticoagulation therapy with warfarin

• Therapeutic anticoagulation with low-molecular weight heparin or heparin allowed
• Mini-dose warfarin (e.g., 1 mg/day) for prophylaxis of central venous catheter thrombosis allowed at the discretion of the treating physician
• No other concurrent anticancer agents, including chemotherapy and biologic agents
• No other concurrent investigational drugs
• No concurrent routine systemic corticosteroid therapy (corticosteroid therapy may only be administered after consultation with the principal investigator)