Association of Capecitabine Pharmacokinetics and Toxicity With Aging

Phase 4

• Conditions: Colorectal Cancer; Breast Cancer
• Interventions: Drug: Capecitabine

• Registration Number: NCT03465202
• Lead Sponsor: Newcastle-upon-Tyne Hospitals NHS Trust

Brief Summary

This is a multi-centre prospective non-interventional study designed to evaluate the effects of patient age on the pharmacokinetics of capecitabine and its metabolites 5'DFCR, 5'DFUR, and 5-FU. In addition, the study will assess the correlation between the pharmacokinetic parameters calculated and cytidine deaminase, biomarkers of aging, clinical frailty, treatment outcome, and toxicity. To be enrolled, patients must have breast or colorectal cancer and be eligible to receive capecitabine monotherapy in accordance with its approved clinical usage in the UK. Treatment will be administered according to NICE guidelines as well as the clinical judgement of the prescribing physician. One hundred patients (50 breast cancer patients, 50 colorectal cancer patients) who are about to start treatment with capecitabine monotherapy will be recruited to the study and undergo study procedures within the first week of treatment.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-08-07
• Study Start: 2016-05
• Status Verified: 2018-03
• Study First Submitted QC: 2018-03-07
• Last Update Submitted: 2018-03-07
• Study First Posted: 2018-03-14
• Last Update Posted: 2018-03-14
• Primary Completion: 2018-05
• Study Completion: 2019-11

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• 1. Histologic or cytologic diagnosis of breast cancer or colorectal cancer. Patients should have disease that is suitable for capecitabine monotherapy as defined by the NICE Guidelines.

  2. Patients must be within the first week of their first cycle of capecitabine treatment.

  3. Estimated life expectancy of greater than 3 months. 4) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 5) Total serum bilirubin less than or equal to 25 micromol/L. 6) Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels less than 2.5 times the upper limit of the normal range.

  4. Serum albumin level greater than 32 g/L. 8) Creatinine clearance greater than or equal to 30 mL/minute. 9) Blood haemoglobin level of greater than 9 g/dL, with transfusion allowed. 10) Absolute neutrophil count greater than 2.5 x 109/L. 11) Platelet count greater than 100 x 109/L. 12) 18 years of age or older. 13) Written informed consent.

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Exclusion Criteria

1. Pregnancy or breast feeding.

2. Known HIV, Hepatitis B, or Hepatitis C infection.

3. Known Gilbert syndrome.

4. Uncontrolled diabetes (HbA1c greater than 7.5%).

5. Any condition or disease that might affect oral absorption of medications, including:

   1. Crohn's disease

   2. Ulcerative colitis

   3. Major gastric or small bowel resection

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Capecitabine	Capecitabine	-

Primary Outcome Measures

Name	Time	Method
Area under the curve (AUC) of capecitabine and metabolites	0 (pre-dose), 0.5, 1, 2, 4, and 6 hours post dose	Measurement of AUC of capecitabine and its metabolites 5'deoxy-5-fluorocytidine (5'DFCR), 5'deoxy-5-fluorouridine (5'DFUR), and 5-fluorouracil.

Secondary Outcome Measures

Name	Time	Method
Grip strength measured in kg	During 6-hour pharmacokinetic study session	Grip strength measured in kg by the grip strength test (using the Takei handheld dynamometer)
Progression free survival as measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1	From time of enrollment until first documented progression	Progression free survival as measured by the RECIST criteria version 1.1 (Eisenhauer et al., 2009). The RECIST criteria define progression as 'at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: the appearance of one or more new lesions is also considered progression)'
Frailty as measured by the Edmonton Frail Scale	During 6-hour pharmacokinetic study session	Frailty as measured by the Edmonton Frail Scale. A 17 point scale that measures 9 frailty domains. 0-5: not frail; 6-7: vulnerable; 8-9: mild frailty; 10-11: moderate frailty; 12-17: severe frailty.
Toxicities and grades as scaled by Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.03	Six months	Toxicity grade(s) as measured by CTCAE version 4.03 (published by the U.S. Department of Heath and Human Services 2009). General grading scheme is as follows: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE.
Plasma cytidine deaminase activity (measured in units/mg protein by spectrophotometric assay)	0 hours post dose (pre-dose)	Plasma cytidine deaminase activity (measured in units/mg protein by spectrophotometric assay).
Maximum plasma concentration (Cmax) of capecitabine and metabolites	0 (pre-dose), 0.5, 1, 2, 4, and 6 hours post dose	Cmax of capecitabine and its metabolites 5'deoxy-5-fluorocytidine (5'DFCR), 5'deoxy-5-fluorouridine (5'DFUR), and 5-fluorouracil.
Response as measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1	From time of enrollment to first documented response	Complete or partial response as measured by the RECIST criteria version 1.1. (Eisenhauer et al., 2009) Complete response = 'Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.; Partial response = 'At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.'
Nutritional status as measured by the Mini Nutritional Assessment questionnaire	During 6-hour pharmacokinetic study session	Nutritional status as measured by the Mini Nutritional Assessment questionnaire, a 30 point test on nutritional status. Scoring: 24 to 30 points: Normal nutritional status.; 17 to 23.5 points: At risk of malnutrition. Less than 17 points: malnourished.
Quality of life as assessed by the European Organization for Research and Treatment of Cancer quality of life (EORTC-QLQ-C30 version 3) questionnaire	During 6-hour pharmacokinetic study session	Quality of life as measured by the EORTC-QLQ-C30 version 3 questionnaire. This questionnaire assesses the quality of life of cancer patients in a series of 30 questions, with 28 of the questions on a scale of 1 to 4 where 1 is 'not at all' and 4 is 'very much'. Final two questions relate to overall quality of life and health on a scale of 1 to 7, where 1 is 'very poor' and 7 is 'excellent'.
Time of maximum plasma concentration (Tmax) of capecitabine and metabolites	0 (pre-dose), 0.5, 1, 2, 4, and 6 hours post dose	Cmax of capecitabine and its metabolites 5'deoxy-5-fluorocytidine (5'DFCR), 5'deoxy-5-fluorouridine (5'DFUR), and 5-fluorouracil.