A Study of Avastin (Bevacizumab) With XELOX or FOLFOX in Patients With Metastatic Colorectal Cancer and Disease Progression Under First-line FOLFIRI and Avastin

Study Overview
=================
Brief Summary
-----------------
This open-label single arm study will evaluate the efficacy and safety of Avastin added to XELOX or FOLFOX in patients with metastatic colorectal cancer and disease progression on 1st line therapy with FOLFIRI plus Avastin. Patients will receive either Avastin (7.5mg/kg iv infusion every 3 weeks) and standard XELOX (Xeloda [capecitabine] plus oxaliplatin) chemotherapy or Avastin (5 mg/kg iv infusion every 2 weeks) and standard FOLFOX (5-FU and leucovorin plus oxaliplatin) chemotherapy. The anticipated time on study treatment is until disease progression, and the target sample size is 100 individuals.

Official Title
-----------------
A Single-arm Open-label Phase II Study: Treatment Beyond Progression by Adding Bevacizumab to XELOX or FOLFOX Chemotherapy in Patients With Metastatic Colorectal Cancer and Disease Progression Under First-line FOLFIRI + Bevacizumab Combination

Conditions
-----------------
Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: fluorouracil (5FU)
* Drug: leucovorin
* Drug: bevacizumab [Avastin]
* Drug: capecitabine [Xeloda]
* Drug: oxaliplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: adult patients >/=18 years of age metastatic colorectal cancer at least 1 measurable lesion according to RECIST v. 1.1 patients with disease progression with prior FOLFIRI + Avastin therapy who are not candidates for primary metastasectomy disease progression </= 8 weeks after last dose of Avastin ECOG </=2 No more than 8 weeks between 1st-line treatment with FOLFIRI + Avastin and 2nd-line treatment with XELOX or FOLFOX + Avastin Exclusion Criteria: disease progression > 8 weeks after last Avastin administration clinically significant cardiovascular disease CNS disease except for treated brain metastasis history of other malignancies within 2 years prior to start of study treatment (with the exception of curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix) major surgery, open biopsy, or significant traumatic injury within 28 days prior to start of study treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avastin (bevacizumab) + standard of care<br> | Drug: fluorouracil (5FU)<br>* standard FOLFOX regimen<br>Drug: leucovorin<br>* standard FOLFOX regimen<br>Drug: bevacizumab [Avastin]<br>* 7.5 mg/kg iv infusion every 3 weeks OR 5 mg/kg iv infusion every 2 weeks<br>Drug: capecitabine [Xeloda]<br>* standard XELOX regimen<br>Drug: oxaliplatin<br>* standard XELOX or FOLFOX regimen<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) From the Start of Treatment Beyond Progression | PFS from the start of treatment beyond progression was defined as the interval between the start of beyond-progression therapy and the date at which disease progression was documented. Progression of disease was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 and abdominal/pelvic computerized tomography (CT) or magnetic resonance imaging (MRI) scanning as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The same method of assessment and the same technique were to be used to evaluate each lesion throughout the entire study. If more than one method was used, data from the most accurate method according to RECIST were recorded. Median PFS was estimated using the Kaplan-Meier method. | Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS From the Start of First-Line Therapy | PFS from the start of first-line therapy was defined as the interval between the start of first-line therapy and the date at which second disease progression (after the start of beyond progression therapy) was documented. Progression of disease was evaluated using RECIST version 1.1 and abdominal/pelvic CT or MRI scanning. The same method of assessment and the same technique were to be used to evaluate each lesion throughout the entire study. If more than one method was used, data from the most accurate method according to RECIST were recorded. Median PFS was estimated using the Kaplan-Meier method. | Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months | 
| Percentage of Participants With an Overall Response of Complete Response (CR) or Partial Response (PR) | Percentage of participants with an overall response of CR or PR according to RECIST criteria. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis less than [<]10 millimeters [mm]). No new lesions. PR was defined as greater than or equal to (≥)30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. | Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months | 
| Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | Pro-angiogenic cytokine concentrations of placental growth factor (PlGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in participant sera were measured and reported in units of picograms/milliliter (pg/mL). The geometric mean was calculated as exp10 (mean of log10 transformed concentration) and the standard deviation (SD) is SD of log10 transformed concentration. | Baseline, every 9 weeks until disease progression, at final visit or at withdrawal, for up to 24 months |