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The purpose of this study is to investigate the influence of dose selection of CPT-11 on toxicity, response and pharmacokinetics according to UGT1A1 genotype in colorectal cancer patients.
Genetic polymorphisms of UGTs result in reduced enzyme activity and increased toxicity. UGT1A1*28 and UGT1A1*6 are reported to increase CPT-11-related toxicity in Asian patients. Moreover, the area under concentration curve (AUC) ratio of SN-38G to SN-38 is decreased in Asian patients having UGT1A1 *28 or UGT1A1*6. This implicated that the current standard dose of CPT-11 would be overdosing for homozygous UGT1A1*28/*28, *6/*6 or *28/*6 patients.
The study is designed to investigate the role of prospectively dose reduction of CPT-11 in toxicity, tumor response and pharmacokinetics for homozygous UGT1A1 patients, and compare these parameters to standard dose of CPT-11 for wild-type, heterozygous or homozygous UGT1A1 patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard FOLFIRI for wild/hetero UGT1A1 | Active Comparator | Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks. |
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| Reduced Dose of CPT-11 for homo UGT1A1 | Experimental | Irinotecan Injection [Camptosar] (CPT-11) 90 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks. |
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| Standard FOLFIRI for homo UGT1A1 | Active Comparator | Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Irinotecan Injection [Camptosar] | Drug | CPT-11 will be administered according to UGT1A1 genotypes. Patients with UGT1A1 *1/*1 or heterozygous UGT1A1*1/*28 or *1/*6 will receive standard dose of CPT-11. Patients with homozygous UGT1A1*28/*28, *6/*6 or *28/*6, will be randomized in a 1:1 ratio to receive standard dose of CPT-11 or 50% reduced dose of CPT-11. |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of toxicity, especially neutropenia and diarrhea | Association between UGT1A1 polymorphism, CPT-11 dosage and incidence of toxicity, especially neutropenia and diarrhea. | From the beginning of treatment to the whole treatment period, an expected average of 6-8 months. |
| Measure | Description | Time Frame |
|---|---|---|
| Response rate | Association between UGT1A1 polymorphism, CPT-11 dosage and tumor response. | Every 6 weeks, an expected average of 6-8 months. |
| Progression-free survival (PFS) | Association between UGT1A1 polymorphism, CPT-11 dosage and PFS. PFS is defined as the length of time from randomise to disease progression or to death from any cause other than progression. |
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Inclusion Criteria:
Histologically confirmed colorectal cancer patients who received no prior chemotherapy or failed to 1st line treatments
At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Aged 18 years or older
ECOG performance status of ≤ 2.
Anticipated life expectancy of ≥ 3 months.
UGT1A1 genotype tested. Categorized into Wild (UGT1A1*1/*1), Hetero (UGT1A1*1/ *28, UGT1A1*1/ *6), and Homo (UGT1A1*28/*28, UGT1A1*6/*6, UGT1A1*28/*6).
Adequate organ function, including bone marrow, kidney and liver.
Written informed consent can be obtained prior to their participation in the trial.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jian-Ming Xu, M.D. | Affiliated Hospital, Academy of Military Medical Sciences | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Affiliated Hospital Cancer Center, Academy of Military Medical Sciences (307 Hospital of PLA) | Beijing | Beijing Municipality | 100071 | China |
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| 5-fluorouracil | Drug | The 5-FU dosage will remain the standard. |
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| Leucovorin | Drug | The LV dosage will remain the standard. |
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| An expected average of 6-8 months. |
| Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G. | Association between UGT1A1 polymorphism, CPT-11 dosage and pharmacokinetics of irinotecan. Plasma concentration of irinotecan and its metabolites, SN-38 and SN-38G are determined using high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS). | The first treatment cycle. |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D009503 | Neutropenia |
| D003967 | Diarrhea |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D000380 | Agranulocytosis |
| D007970 | Leukopenia |
| D000095542 | Cytopenia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007960 | Leukocyte Disorders |
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000077146 | Irinotecan |
| D005472 | Fluorouracil |
| D002955 | Leucovorin |
| ID | Term |
|---|---|
| D002166 | Camptothecin |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D005575 | Formyltetrahydrofolates |
| D013763 | Tetrahydrofolates |
| D005492 | Folic Acid |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D003067 | Coenzymes |
| D045762 | Enzymes and Coenzymes |
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