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

Study Overview
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Brief Summary
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RATIONALE: Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving imatinib mesylate together with gemcitabine and capecitabine may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of gemcitabine and capecitabine when given together with imatinib mesylate in treating patients with advanced solid tumors.

Detailed Description
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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.

Official Title
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Phase I Study of Imatinib, Gemcitabine and Capecitabine in Patients With Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: capecitabine
* Drug: gemcitabine hydrochloride
* Drug: imatinib mesylate
* Genetic: mutation analysis
* Genetic: nucleic acid sequencing
* Genetic: polymerase chain reaction


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 19 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 |
| --- | --- |
| Other: Imatinib/Gemcitabine/Capecitabine<br>Patients will be accrued on cohorts of three per dose level starting at dose level 0. Accrual to higher dose levels will depend on toxicity occurrence. Dose limiting toxicity (DLT) will be determined after cycle two for each patient. Schema: Imatinib days 1 - 5 and days 8 - 12 Gemcitabine on days 3 and 10 Capecitabine on days 1 - 14 Doses: Imatinib 400 mg/d fixed dose Gemcitabine 450 mg/m2; 550 mg/m2; 675 mg/m2; 825 mg/m2; 1000 mg/m2 Capecitabine 500 mg/m2; 600 mg/m2 bid; 725 mg/m2; 850 mg/m2 Treatment cycle: 21-days Treatment duration: Until disease progression or unacceptable toxicity defined in protocol. | Drug: capecitabine<br>* Dose level Capecitabine -1 400 mg/m2 bid 0 500 mg/m2 bid 500 mg/m2 bid 600 mg/m2 bid 600 mg/m2 bid 725 mg/m2 bid 725 mg/m2 bid 850 mg/m2 bid 850 mg/m2 bid<br>* Other names: Xeloda;Drug: gemcitabine hydrochloride<br>* Dose level Gemcitabine -1 400 mg/m2 0 450 mg/m2 550 mg/m2 550 mg/m2 675 mg/m2 675 mg/m2 825 mg/m2 825 mg/m2 1000 mg/m2<br>* Other names: Gemzar;Drug: imatinib mesylate<br>* Dose level Imatinib -1 400 mg/d 0 400 mg/d 400 mg/d 400 mg/d 400 mg/d 400 mg/d 400 mg/d 400 mg/d 400 mg/d<br>* Other names: Gleevec;Genetic: mutation analysis<br>* C-kit mutations will be assessed on existing paraffin-embedded blocks by Polymerase Chain Reaction and direct sequencing of both juxtamembrane domains (exons 9 and 11) and the tyrosine kinase domain (exons 13 and 17). Every ABI sequence will be compared to a NCBI Human KIT gene nucleotide sequence and will be blast using a NCBI Standard Nucleotide Blast Search to determine the presence of mutation within a particular exon.<br>Genetic: nucleic acid sequencing<br>* C-kit mutations will be assessed on existing paraffin-embedded blocks by Polymerase Chain Reaction and direct sequencing of both juxtamembrane domains (exons 9 and 11) and the tyrosine kinase domain (exons 13 and 17). Every ABI sequence will be compared to a NCBI Human KIT gene nucleotide sequence and will be blast using a NCBI Standard Nucleotide Blast Search to determine the presence of mutation within a particular exon.<br>Genetic: polymerase chain reaction<br>* C-kit mutations will be assessed on existing paraffin-embedded blocks by Polymerase Chain Reaction and direct sequencing of both juxtamembrane domains (exons 9 and 11) and the tyrosine kinase domain (exons 13 and 17). Every ABI sequence will be compared to a NCBI Human KIT gene nucleotide sequence and will be blast using a NCBI Standard Nucleotide Blast Search to determine the presence of mutation within a particular exon.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of gemcitabine hydrochloride and capecitabine when combined with imatinib mesylate | Cohorts of 3 starting at dose level 0. The imatinib dose is fixed. The dose of capecitabine is initially fixed and the dose of gemcitabine is increased 1 dose level. For the subsequent cohort, the dose of gemcitabine will be fixed and the dose of capecitabine advanced to the next dose level. 3 patients will be treated on the initial schedule. If no dose-limiting toxicities related to drug are observed and no patients require dose mods by the end of cycle 2, then 3 patients will be treated on the next schedule. | By the end of cycle 2 | 
| Dose-limiting Toxicity | Cohorts of 3 starting at dose level 0. The imatinib dose is fixed. The dose of capecitabine is initially fixed and the dose of gemcitabine is increased 1 dose level. For the subsequent cohort, the dose of gemcitabine will be fixed and the dose of capecitabine advanced to the next dose level. 3 patients will be treated on the initial schedule. If no dose-limiting toxicities related to drug are observed and no patients require dose mods by the end of cycle 2, then 3 patients will be treated on the next schedule. | By the end of cycle 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor activity | Deidentified melanoma samples will be sent to our collaborator at Ohio State, Dr. Christopher Corless, who is a recognized expert in this field. Renal cell samples will be assayed here at our institution | Following response assessment. | 

 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