Maintenance Treatment Versus Observation After Induction in Advanced Colorectal Carcinoma

Colorectal Cancer Metastatic Clinical Trial

— CAIRO3  

Official title:

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

Clinical Trial Details — Status: Unknown status

Administrative data

• NCT number: NCT00442637
• Other study ID #: CAIRO3
• Status: Unknown status
• Phase: Phase 3
• First received: February 28, 2007
• Last updated: December 11, 2013
• Start date: January 2007
• Est. completion date: December 2013

Study information

• Verified date: December 2013
• Source: Dutch Colorectal Cancer Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The optimal duration of systemic treatment in patients with advanced colorectal cancer is unknown.

In this study the effects of bevacizumab and low-dose continuous chemotherapy with capecitabine is investigated in patients who have responded to 6 courses of oxaliplatin, capecitabine and bevacizumab ("induction treatment", at standard doses). This treatment is continued until progression or severe toxicity. This regimen is compared to the effects a observation without treatment after the induction treatment.

In case of disease progression, induction treatment will be reintroduced.

Description:

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.

Recruitment information / eligibility

• Status: Unknown status
• Enrollment: 635
• Est. completion date: December 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 Avastin.

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 therapy;

• 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 tablets);

• 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).

Related Conditions & MeSH terms

• Colorectal Cancer Metastatic
• Colorectal Neoplasms

Intervention

Drug:
• capecitabine + bevacizumab
Ca 1250 mg/m2 daily orally continuously, B 7.5 mg/kg i.v. q 3 w

Other:
• observation
observation after induction treatment

Locations

Country	Name	City	State
Netherlands	University Medical Center Nijmegen	Nijmegen	Gelderland

Sponsors (4)

Lead Sponsor	Collaborator
Dutch Colorectal Cancer Group	Hoffmann-La Roche, Koningin Wilhelmina Fonds, Sanofi

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival after re-introduction of MTD chemotherapy and bevacizumab (PFS2)		study duration
Secondary	Progression-free survival between observation versus maintenance therapy (PFS1)		study duration
Secondary	Response rate during re-introduction of MTD chemotherapy and bevacizumab		study duration
Secondary	Toxicity		study duration
Secondary	Quality of life		study duration
Secondary	Overall survival		study duration
Secondary	Translational research		study duration

External Links

•   Dutch Colorectal Cancer Group