A Study of Avastin (Bevacizumab) in Combination With XELOX or FOLFOX-4 in Patients With Metastatic Colorectal Cancer.

Conditions

Colorectal Cancer

Brief summary

This 2 arm study will compare the pharmacokinetics and safety of Avastin at steady state under 2 different dosing regimens, in combination with XELOX (oxaliplatin + Xeloda) or FOLFOX-4 (oxaliplatin, leucovorin and 5-fluorouracil). Patients randomized to the XELOX arm will receive Avastin (7.5mg/kg iv) on Day 1 of each 3 week cycle; patients randomized to the FOLFOX-4 arm will receive Avastin (5mg/kg iv) on Day 1 of each 2 week cycle. The anticipated time on study treatment is 3-12 months, and the target sample size is \<100 individuals.

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Interventions

DRUGbevacizumab [Avastin]

7.5mg/kg iv on day 1 of each 3 week cycle

DRUGXELOX

As prescribed

DRUGFOLFOX-4

As prescribed

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* adult patients, \>=18 years of age; * adenocarcinoma of the colon or rectum, with metastatic or locally advanced disease; * \>=1 target lesion.

Exclusion criteria

* patients who have previously received systemic treatment for advanced or metastatic disease; * patients who have received adjuvant treatment for non-metastatic disease in past 3 months; * previous therapy with oxaliplatin or Avastin.

Design outcomes

Primary

Measure	Time frame	Description
Weekly Steady-state Exposure of Bevacizumab	Up to 48 weeks	Area under the serum concentration-time curve per week, at steady state (AUCss per week). Estimation of the parameter was performed using non-compartmental methods.

Secondary

Measure	Time frame	Description
Steady-state Exposure of Bevacizumab From Time Zero to Tau	Up to 48 weeks	Area under the serum concentration-time curve from time zero to tau, at steady state (AUCss 0-tau), where tau was the length of the cycle, i.e., tau = 3 weeks for XELOX+BV and tau = 2 weeks for FOLFOX-4+BEV. Estimation of the parameter was performed using non-compartmental methods.
Maximum Serum Concentration of Bevacizumab at Steady State	Up to 48 weeks	Maximum serum concentration at steady state (Css,max). Estimation of the parameter was performed using non-compartmental methods.
Minimum Serum Concentration of Bevacizumab at Steady State	Up to 48 weeks	Minimum serum concentration at steady state (Css, min). Estimation of the parameter was performed using non-compartmental methods.
Time Zero to Last Measurable Plasma Concentration of Bevacizumab	Up to 48 weeks	Area under the serum concentration-time curve from time zero to the time of the last measurable plasma concentration (AUC 0-last). Estimation of the parameter was performed using non-compartmental methods.
Time of Maximum Serum Concentration of Bevacizumab	Up to 48 weeks	Time of maximum serum concentration (tmax). Estimation of the parameter was performed using non-compartmental methods.
Volume of Distribution of Bevacizumab at Steady State	Up to 48 weeks	Volume of distribution at steady state (Vss). Estimation of the parameter was performed using non-compartmental methods.
Terminal Half-life of Bevacizumab	Up to 48 weeks	Terminal half-life (t1/2) (apparent elimination half-life). Estimation of the parameter was performed using non-compartmental methods.
Serum Clearance of Bevacizumab	Up to 48 weeks	Serum clearance (CL). Estimation of the parameter was performed using non-compartmental methods.

Countries

Australia, Canada, New Zealand

Participant flow

Recruitment details

A total of 64 patients in 7 centers were enrolled between 01 August 2006 to 28 May 2008. 37 were included in the pharmacokinetic (PK) analyses.

Participants by arm

Arm	Count
XELOX+Bevacizumab XELOX regimen = oxaliplatin in combination with capecitabine. Bevacizumab 7.5 mg/kg IV followed by oxaliplatin 130 mg/m² IV on Day 1 in combination with capecitabine, administered orally at a dose of 1000 mg/m² twice daily (BID); 3-week cycles up to 48 weeks (Cycle 16).	32
FOLFOX-4+Bevacizumab FOLFOX-4 regimen = oxaliplatin in combination with infusional 5-fluorouracil and leucovorin. Bevacizumab 5.0 mg/kg IV followed by oxaliplatin 85 mg/m² IV on Day 1 concomitantly with leucovorin 200 mg/m² IV, followed by 5-fluorouracil administered as a 400 mg/m² bolus injection, and then as a 600 mg/m² continuous infusion on Days 1 and 2; 2-week cycles for up to 48 weeks (Cycle 24).	32
Total	64

Baseline characteristics

Characteristic	XELOX+Bevacizumab	FOLFOX-4+Bevacizumab	Total
Age Continuous	55.9 years STANDARD_DEVIATION 12.56	57.9 years STANDARD_DEVIATION 10.84	56.9 years STANDARD_DEVIATION 11.74
Sex: Female, Male Female	13 Participants	17 Participants	30 Participants
Sex: Female, Male Male	19 Participants	15 Participants	34 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	32 / 32	32 / 32
serious Total, serious adverse events	9 / 32	15 / 32

Outcome results

Primary

Weekly Steady-state Exposure of Bevacizumab

Area under the serum concentration-time curve per week, at steady state (AUCss per week). Estimation of the parameter was performed using non-compartmental methods.

Time frame: Up to 48 weeks