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Maintenance Treatment With Capecitabine and Bevacizumab Versus Observation After Induction Treatment With Chemotherapy and Bevacizumab as First-line Treatment in Patients With Advanced Colorectal Carcinoma

Phase 3
18 Years
Open (Enrolling)
Colorectal Cancer Metastatic

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Trial Information

Maintenance Treatment With Capecitabine and Bevacizumab Versus Observation After Induction Treatment With Chemotherapy and Bevacizumab as First-line Treatment in Patients With Advanced Colorectal Carcinoma

Standard 1st-line treatment for patients with advanced colorectal cancer currently consists
of chemotherapy plus bevacizumab. With this approach the median overall survival is
approximately 20 months, and progression-free survival in first-line approximately 9-11
months. The optimal duration of treatment is unknown. Current data suggest that the efficacy
of bevacizumab is dependent on concomitant use of chemotherapy. However, oxaliplatin almost
invariably gives rise to neuropathy after 6-8 cycles. Prolonged use of capecitabine is
associated with e.g. hand-foot syndrome. Lastly, the prolonged use of these agents is
associated with considerable costs.

Evidence, mainly preclinical, suggests that continuous dosing metronomic chemotherapy may be
more efficacious than interval-chemotherapy given at MTD. In this study the concept of
metronomic chemotherapy is explored by administering a continuous daily instead of the usual
2 weeks-on/1 week-off oral dosing regimen of low-dose capecitabine plus bevacizumab as
maintenance therapy after induction combination chemotherapy given at MTD plus bevacizumab.

Before the start of induction therapy:

Inclusion Criteria:

- Histological proof of colorectal cancer (in case of a single metastasis, histological
or cytological proof of this lesion should be obtained);

- Distant metastases (patients with only local recurrence are not eligible);

- Unidimensionally measurable disease (> 1 cm on spiral CT scan or > 2 cm on chest
X-ray; liver ultrasound is not allowed). Serum CEA may not be used as a parameter for
disease evaluation;

- In case of previous radiotherapy, at least one measurable lesion should be located
outside the irradiated field.

- Ongoing or planned first line treatment with 6 cycles of Xeloda, Eloxatin, and

Exclusion criteria

- Prior adjuvant treatment for stage II/III colorectal cancer ending within 6 months
before the start of induction treatment

- Any prior adjuvant treatment after resection of distant metastases

- Previous systemic treatment for advanced disease

At randomisation:

Inclusion criteria:

- WHO performance status 0-1 (Karnofsky PS > 70%);

- Disease evaluation with proven SD, PR or CR according to RECIST after 6 cycles of MTD
chemotherapy performed in week 3-4 of the 6th cycle induction therapy, and
randomisation performed in week 3-5 of the 6th cycle (see time table);

- Laboratory values obtained ≤ 2 weeks prior to randomisation: adequate bone marrow
function (Hb > 6.0 mmol/L, absolute neutrophil count > 1.5 x 109/L, platelets > 100 x
109/L), renal function (serum creatinine ≤ 1.5x ULN and creatinine clearance,
Cockroft formula, > 30 ml/min), liver function (serum bilirubin ≤ 2 x ULN, serum
transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with
presence of liver metastases);

- Life expectancy > 12 weeks;

- Age >= 18 yrs;

- Negative pregnancy test in women with childbearing potential;

- Expected adequacy of follow-up;

- Institutional Review Board approval;

- Written informed consent Exclusion criteria

- History or clinical signs/symptoms of CNS metastases;

- History of a second malignancy ≤ 5 years with the exception of adequately treated
carcinoma of cervix or basal/squamous cell carcinoma of skin;

- Previous intolerance of XelodaR, EloxatinR, and/or AvastinR for which any of these
drugs have been permanently discontinued; patients with previous dose reductions or
delays are eligible; patients with grade 2 neurotoxicity after the 6th cycle are
eligible, and retreatment with EloxatinR after PFS1 should depend on the grade of
neurotoxicity at that moment;

- Known dihydropyrimidine dehydrogenase (DPD) deficiency;

- (Planned) radical resection of all metastatic disease;

- Uncontrolled hypertension, i.e. consistently > 150/100 mmHg;

- Use of more than 3 antihypertensive drugs;

- Significant cardiovascular disease < 1 yr before randomisation (symptomatic
congestive heart failure, myocardial ischemia or infarction, unstable angina
pectoris, serious uncontrolled cardiac arrhythmia, arterial thrombosis,
cerebrovascular event, pulmonary embolism);

- Any of these significant cardiovascular events during previous fluoropyrimidine

- Chronic active infection;

- Any other concurrent severe or uncontrolled disease preventing the safe
administration of study drugs;

- Any impairment of gastrointestinal function or -disease that may significantly impair
the absorption of oral drugs (i.e. uncontrolled nausea, vomiting, diarrhoea (defined
as >CTC grade 2), malabsorption syndrome, bowel obstruction, or inability to swallow

- Concomitant treatments: concomitant (or within 4 weeks before randomisation)
administration of any other experimental drug under investigation; concurrent
treatment with any other anti-cancer therapy; full-dose anticoagulation (is allowed
if started during induction therapy);

- Continuous use of immunosuppressive agents (except the use of corticosteroids as
anti-emetic prophylaxis/treatment).

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival after re-introduction of MTD chemotherapy and bevacizumab (PFS2)

Outcome Time Frame:

study duration

Safety Issue:


Principal Investigator

C. JA Punt, MD PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Amsterdam Medical Centre, Amsterdam Netherlands


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

January 2007

Completion Date:

June 2013

Related Keywords:

  • Colorectal Cancer Metastatic
  • CAIRO3
  • DCCG
  • colorectal cancer
  • induction
  • metronomic chemotherapy
  • observation
  • capecitabine
  • bevacizumab
  • oxaliplatin
  • Carcinoma
  • Colorectal Neoplasms
  • Neoplasms
  • Neoplasms, Second Primary