Irinotecan, Oxaliplatin, and Capecitabine in Treating Patients With Unresectable Solid Tumors

Study Overview
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Brief Summary
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Drugs used in chemotherapy, such as irinotecan, oxaliplatin, and capecitabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one chemotherapy drug may kill more tumor cells. This phase I trial is studying the side effects and best dose of irinotecan, oxaliplatin, and capecitabine in treating patients with unresectable solid tumors.

Detailed Description
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OBJECTIVES: I. To define the maximally tolerated dose of the combination of CPT-11 (irinotecan hydrochloride), oxaliplatin, and capecitabine in three different populations, based on UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotype (6/6, 6/7, and 7/7). II. To identify any activity of this treatment combination in patients with metastatic cancer. III. To examine the differences in the toxicity profile, especially pertaining to hematologic and gastrointestinal (GI), and the maximally tolerated dose of the combination of CPT-11, oxaliplatin and capecitabine with respect to the UGT1A1 haplotypes. IV. Examine the effect of the UGT1A1 genotype on the pharmacokinetics of CPT-11 and its metabolites. OUTLINE: This is a dose-escalation study. Patients are stratified according to UGT1A1 genotype (6/6 vs 6/7 [closed to accrual as of 8/24/06] vs 7/7). Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes and oxaliplatin IV over 2 hours on day 1 and capecitabine orally (PO) twice daily (QD) on days 2-15. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan hydrochloride, oxaliplatin, 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. Once the MTD is determined, an additional 6-10 patients (for a total of 12 patients) receive treatment at that dose. After completion of study treatment, patients are followed up at 3 months. PROJECTED ACCRUAL: A total of 54-84 patients (12-22 for stratum I, 18-28 for stratum II [closed to accrual as of 8/24/06], and 24-34 for stratum III) will be accrued for this study within approximately 4.4 years.

Official Title
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A Phase I And Pharmacogenetic Study Of CPT-11, Oxaliplatin, 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: irinotecan hydrochloride
* Drug: oxaliplatin
* Drug: capecitabine
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumor for which there is no known standard therapy that is potentially curative or capable of extending life expectancy Unresectable disease Willing to provide biologic specimens to determine UGT1A1 genotype No CNS metastases Prior CNS metastases allowed provided patient was treated with surgery and/or radiotherapy and is stable for more than 8 weeks Performance status - ECOG 0-2 At least 12 weeks Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin at least 9.0 g/dL Bilirubin no greater than upper limit of normal (ULN) for patients with 6/6 UGT1A1 genotype (1.5 times ULN for patients with 6/7 [closed to accrual as of 8/24/06] or 7/7 UGT1A1 genotype) AST no greater than 3 times ULN (5 times ULN if there is liver involvement) Creatinine no greater than 1.5 times ULN No New York Heart Association class III or IV heart disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior allergy to platinum compounds, irinotecan, or to antiemetics or antidiarrheals appropriate for administration with study therapy No uncontrolled infection No seizure disorder No peripheral neuropathy grade 2 or greater More than 4 weeks since prior biologic therapy More than 4 weeks since prior immunotherapy No concurrent immunotherapy No concurrent prophylactic colony-stimulating factor therapy More than 4 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered No other concurrent chemotherapy See Disease Characteristics More than 4 weeks since prior radiotherapy No prior radiotherapy to more than 25% of the bone marrow No concurrent radiotherapy See Disease Characteristics No other concurrent investigational therapy No concurrent sorivudine, brivudine, lamivudine, or stavudine No concurrent enrollment in any other study involving a pharmacologic agent for symptom control or therapeutic intent

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Arm I<br>Patients receive irinotecan hydrochloride IV over 90 minutes and oxaliplatin IV over 2 hours on day 1 and capecitabine PO QD on days 2-15. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: capecitabine<br>* Given PO<br>* Other names: Xeloda;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined as one dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) assessed using NCI CTCAE v3.0 |  | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of UTG1A1*28 polymorphism | The overall incidence of UTG1A1*28 polymorphism will be estimated and summarized in this patient population. In addition, the incidence of this polymorphism will be explored in relation to tumor type. | Up to 3 months | 
| Adverse events profile assessed using NCI CTCAE v3.0 | The number and severity of all adverse events (overall, by dose level, and by tumor group) will be tabulated and summarized for the three patient groups. The grade 3+ adverse events will also be described and summarized in a similar fashion. | Up to 3 months | 
| Toxicity profile assessed using NCI CTCAE v3.0 | Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized in each of the two groups. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. | Up to 3 months | 
| Response profile using RECIST criteria | Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as table and progressive disease in the two patient populations (overall and by tumor group). | Up to 3 months | 
| Time until any treatment related toxicity | Will be summarized descriptively. | Up to 3 months | 
| Time until treatment related grade 3+ toxicity | Will be summarized descriptively. | Up to 3 months | 
| Time until hematologic nadirs (WBC, ANC, platelets) | Will be summarized descriptively. | Up to 3 months | 
| Time to progression | Will be summarized descriptively. | Up to 3 months | 
| Time to treatment failure | Will be summarized descriptively. | From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 3 months |