Clinical Trial Result Information

Title of Study:
An open label multi-center trial to assess the pharmacokinetic interaction between capecitabine and oxaliplatin in patients with metastatic colorectal cancer.

Fast Facts:

Protocol number:	NP18587
Sponsor:	Hoffmann-La Roche
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	III
Therapeutic area, approved indication:	Colorectal Cancer
Date of report:	12/1/2006

Clinical study summary:
This study was an open label, multi-center study consisting of a single treatment regimen. Patients with metastatic colorectal cancer received treatment with Xeloda and oxaliplatin for up to 16 Cycles and pharmacokineitc assessments were performed during Cycles 1, 2 and 3.

Study center(s) :
Three centers in Canada.

Objectives:
The objectives of this study were as follows: to determine whether oxaliplatin influences the pharmacokinetics of capecitabine; to determine whether capcitabine influences the pharmacokinetics of oxaliplatin; to determine whether the combination of oxaliplatin and bevacizumab influences the pharmacokinetics of capecitabine; to determine whether the combination of capecitabine and bevacizumab influences the pharmacokinetics of oxaliplatin; to determine whether bevacizumab influences the pharmacokinetics of oxaliplatin in the presence of capecitabine; to determine whether bevacizumab influences the pharmacokinetics of capecitabine in the presence of oxaliplatin.

Methodology:
Cycle 1: A single oral dose of Xeloda 1000 mg/m² was administered on the morning of Day 1. Oxaliplatin 130 mg/m² was administered as a 2h intravenous infusion on Day 2 followed by oral dosing of Xeloda beginning on Day 5 and extending through the evening of Day 14. Xeloda was dosed at 1000 mg/m² twice-daily.

Cycle 2: On Day 1, oxaliplatin 130 mg/m² was administered as a 2h intravenous infusion in combination with Xeloda, which was administered orally at a dose of 1000 mg/m² twice-daily. The first dose of Xeloda was administered in the morning of Day 1 and the last dose was administered on the evening of Day 14.

Cycle 3: On Day 1, Avastin (bevacizumab) 7.5 mg/kg was administered as a 90 min intravenous infusion concurrently with oxaliplatin 130 mg/m² administered as a 2h intravenous infusion (Day 1 every 3 weeks) in combination with Xeloda, which was administered orally at a dose of 1000 mg/m² twice daily, with first dose on the morning of Day 1 and last dose the evening of Day 14. Due to the incompatibility of the Avastin and oxaliplatin infusion solutions, they were administered via separate lines to prevent any interaction of the solutions. Cycle 3 treatments were to continue for a further 13 cycles (i.e. up until cycle 16) or until progressive disease was documented, unacceptable toxicity was encountered, or until the patient withdrew his/her consent.

Pharmacokinetic assessments were performed during Cycles 1, 2 and 3 of treatment. During Cycle 1 a single dose of Xeloda 1000 mg/m² was administered in the morning of Day 1 and from this dose, pharmacokinetic assessments of Xeloda and its metabolites were performed. Blood sampling for the determination of Xeloda and its metabolites occurred pre-dose, and at intervals up to 12 hours post the dose. Blood sampling for the determination of total and free platinum occurred pre-dose and at intervals up to 72 hours from the beginning of the two hour oxaliplatin infusion. The 72 hour sample was taken before the morning dose of Xeloda was administered on Day 5.

During Cycles 2 and 3 blood sampling for the determination of Xeloda and its metabolites occurred pre-dose and at intervals up to 12 hours post the Day 1 morning dose of Xeloda. Blood sampling for pharmacokinetic parameters of total and free platinum occurred pre-dose and at intervals up to 72 hours from the beginning of the two hour oxaliplatin infusion.
If patients received dose reductions or were discontinued during Cycles 1-3, they were no longer evaluable for the pharmacokinetic analysis.

Number of patients (planned/analyzed):
36 enrolled; 26 in pharmacokinetic analysis

Diagnosis and main criteria for inclusion:
Male and female outpatients ≥18 year, ECOG performance status ≤1, with histologically or cytologically confirmed adenocarcinoma of the colon or rectum with metastatic or locally advanced disease.

Test product, dose and mode of administration or test procedure:
Xeloda (capecitabine) was administered orally at a dose of 1000 mg/m² once or twice daily.
Oxaliplatin was administered intravenously at a dose of 130 mg/m² over 2h.
Avastin (bevacizumab) was administered intravenously at a dose of 7.5 mg/kg over 90 minutes.

Duration of treatment:
Up to 16 x 2 week cycles of treatment.

Criteria for evaluation (efficacy, safety):
Pharmacokinetics: Capecitabine: Primary: AUC_0-∞ of 5’-DUR.
Secondary: AUC_0-∞, AUC_0-last, C_max, and t_½,β of capecitabine and its metabolites (5’-DFCR, 5-FU, and FBAL); AUC_0-last, C_max, and t_½,β of 5’-DFUR.
Oxaliplatin: Primary: AUC_0-∞ of free platinum.
Secondary: AUC_0-∞, C_max, AUC_0-last, t_½, V_ss and CL of total platinum; C_max, AUC_0-last, t_½, V_ss and CL of free platinum.

Safety: Adverse events and laboratory tests, graded according to the NCI CTCAE (version 3.0).

Statistical methods:
The goal of the statistical analyses was not to formally prove that the agents do not impact on each other, but rather to characterize a possible effect on their pharmacokinetic parameters. As a consequence no formal statistical testing was conducted.

Summary (efficacy, safety, other results):
Pharmacokinetic: The primary parameter for evaluation of the effect of oxaliplatin or oxaliplatin and bevacizumab in the pharmacokinetics of capecitabine was AUC_0-∞ of 5'DFUR, which is the direct precursor of 5-FU and, therefore, is considered to be the most important metabolite of capecitabine.
The extent of exposure of 5'-DFUR was slightly lower in both Cycle 2, Day 1 (capecitabine and oxaliplatin) and Cycle 3, Day 1 (capecitabine, oxaliplatin and bevacizumab) compared with Cycle 1, Day 1 (capecitabine alone). Also, the rate of absorption (C_max) of 5’-DFUR decreased in Cycles 2 and 3. The impact of these observed differences on the clinical outcome is currently unknown.
The extent of exposure of capecitabine was slightly higher in both Cycle 2, Day 1 and Cycle 3, Day 1 compared with Cycle 1, Day 1. The rate of absorption of capecitabine however, was slightly lower.
For the other metabolites (5'DFCR, 5-FU, FBAL), the AUC_0-∞ and C_max was lower on Cycle 2, Day 1 and Cycle 3 Day 1 compared with Cycle 1 Day 1. These small differences are considered to be clinically insignificant.
AUC_0-∞ and C_max of capecitabine and 5’-DFCR showed a slight increase, and that of 5’DFUR, 5-FU and FBAL showed a slight decrease in Cycle 3, Day 1 compared to Cycle 2, Day 1. Overall the changes were small and not considered to be of clinical significance.
The median time to reach maximum concentration remained unchanged from cycle to cycle.
The elimination half-lives of capecitabine and its metabolites were highly consistent among treatment cycles, indicating that co-administration with oxaliplatin or oxaliplatin and bevacizumab did not alter the elimination process of capecitabine.
Overall, the exposure and other pharmacokinetic parameters of free platinum were very similar between Cycle 1, Day 2 (capecitabine and oxaliplatin), Cycle 2, Day 1 (oxaliplatin alone), and Cycle 3, Day 1 (capecitabine, oxaliplatin, and bevacizumab), with the geometric mean ratios for the three pairwise comparisons for both AUC_0-∞ and C_max being very close to 1. For any of the six 90% confidence intervals, the lowest lower limit was 0.91 and the highest upper limit was 1.09. Therefore, neither capecitabine, the combination of capecitabine and bevacizumab, nor bevacizumab in the presence of capecitabine are considered to influence the pharmacokinetics of oxaliplatin.
The AUC_0-∞ of total platinum was slightly higher in Cycle 2, Day 1 and Cycle 3, Day 1 as compared to Cycle 1, Day 2. However, this is not considered to be clinically meaningful due to both the modest size of the increase and the fact that free platinum concentrations are more representative of the therapeutic exposure to oxaliplatin than total platinum concentrations. The C_max, AUC_0-∞ and other pharmacokinetic parameters of total platinum were similar between Cycle 2, Day 1 and Cycle 3, Day 1.

Safety: Treatment with Xeloda, oxaliplatin and Avastin in combination was generally well tolerated with no or new unexpected safety findings. The most common AEs were gastrointestinal disorders and the single most common AE reported was diarrhea.
Up to clinical cut-off, there were no deaths reported in this study. Twelve patients experienced a total of 18 serious adverse events, of which 13 were considered related to trial treatment by the investigator. These were dehydration (4 patients), diarrhea (3 patients), gastrointestinal hemorrhage (1 patient), thrombocytopenia (1 patient), pyrexia (1 patient), abdominal pain (1 patient), enteritis (1 patient) and neutropenia (1 patient). One patient was withdrawn prematurely due to SAEs of enteritis and neutropenia and another was withdrawn due to right arm dysesthesia. Laboratory results were unremarkable and there were no clinically significant changes in vital signs.

Conclusions:
No clinically relevant differences in exposure of capecitabine or its metabolites, free platinum or total platinum, occur when Xeloda, oxaliplatin and Avastin are administered in combination. There were no new or unexpected safety findings.

Click here for the protocol registry listing of this trial.