Association of Capecitabine Pharmacokinetics and Toxicity With Aging

A Prospective Evaluation of Capecitabine and Metabolite Pharmacokinetics in Elderly Breast and Colorectal Cancer Patients and Their Association With Toxicity and Molecular Markers of Enzyme Activity and Aging

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.

Study Overview

• Status: Unknown
• Conditions: Breast Cancer; Colorectal Cancer
• Intervention / Treatment: Drug: Capecitabine

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

  7) 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.

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Capecitabine	Drug: Capecitabine; Other Names: Xeloda

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicities and grades as scaled by Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.03	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.	Six months
Progression free survival as measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1	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)'	From time of enrollment until first documented progression
Response as measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1	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.'	From time of enrollment to first documented response
Grip strength measured in kg	Grip strength measured in kg by the grip strength test (using the Takei handheld dynamometer)	During 6-hour pharmacokinetic study session
Frailty as measured by the Edmonton Frail Scale	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.	During 6-hour pharmacokinetic study session
Nutritional status as measured by the Mini Nutritional Assessment questionnaire	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.	During 6-hour pharmacokinetic study session
Quality of life as assessed by the European Organization for Research and Treatment of Cancer quality of life (EORTC-QLQ-C30 version 3) questionnaire	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'.	During 6-hour pharmacokinetic study session
Plasma cytidine deaminase activity (measured in units/mg protein by spectrophotometric assay)	Plasma cytidine deaminase activity (measured in units/mg protein by spectrophotometric assay).	0 hours post dose (pre-dose)
Maximum plasma concentration (Cmax) of capecitabine and metabolites	Cmax of capecitabine and its metabolites 5'deoxy-5-fluorocytidine (5'DFCR), 5'deoxy-5-fluorouridine (5'DFUR), and 5-fluorouracil.	0 (pre-dose), 0.5, 1, 2, 4, and 6 hours post dose
Time of maximum plasma concentration (Tmax) of capecitabine and metabolites	Cmax of capecitabine and its metabolites 5'deoxy-5-fluorocytidine (5'DFCR), 5'deoxy-5-fluorouridine (5'DFUR), and 5-fluorouracil.	0 (pre-dose), 0.5, 1, 2, 4, and 6 hours post dose

Collaborators and Investigators

• Sponsor: Newcastle-upon-Tyne Hospitals NHS Trust
• Collaborators: University of Newcastle Upon-Tyne

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Anticipated): May 1, 2018
• Study Completion (Anticipated): November 1, 2019

Study Registration Dates

• First Submitted: August 7, 2015
• First Submitted That Met QC Criteria: March 7, 2018
• First Posted (Actual): March 14, 2018

Study Record Updates

• Last Update Posted (Actual): March 14, 2018
• Last Update Submitted That Met QC Criteria: March 7, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Capecitabine; Colorectal cancer; Ageing; Pharmacokinetics; Breast cancer; Frailty
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine
• Other Study ID Numbers: SBRU201501