Ignite Creation Date:
2024-05-05 @ 5:23 PM
Last Modification Date:
2024-10-26 @ 9:31 AM
Study NCT ID:
NCT00444041
Status:
COMPLETED
Last Update Posted:
2013-01-30
First Post:
2007-03-05
Brief Title:
Pre- and Postoperative Chemotherapy Including Bevacizumab in Potentially Curable Metastatic Colorectal Cancer
Sponsor:
Austrian Society Of Surgical Oncology
Organization:
Austrian Society Of Surgical Oncology
Study Overview
Official Title:
Pre- and Postoperative Chemotherapy Including Bevacizumab in Potentially Curable Metastatic Colorectal Cancer mCRC A Multicenter Single Arm Phase III Academic Trial
Status:
COMPLETED
Status Verified Date:
2013-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ASSO-LM1
Brief Summary:
Major attempt is being given to the potential of curing patients with metastatic colorectal cancer due to the recognition of dramatic change in survival figures achieved in palliative chemotherapy combination treatment protocols Achieving resectablity rates in previously unresectable patients has been defined as study endpoint among other well known primary and secondary objectives Curing metastatic colorectal cancer is most likely in resectable patients and therefore the logical next step after completion of chemotherapy combination studies eg EORTC 40983 is the addition of targeted agents Bevacizumab has the most valid data of improving outcome figures and was therefore chosen as additional agent Safety of the combination with Xelox was demonstrated in the investigators pilot trial Gruenberger JCO 2006 ASCO 2006 WCGC 2006 ESMO 2006 consequently response rate and resection rate will be the primary endpoints in this trial
STUDY OBJECTIVES
Primary Objective The primary objective of this study is the Resectability R0 rate after neoadjuvant Bevacizumab in potentially resectable mCRC
Secondary Objectives The secondary objectives of this study include
Feasibility with regards to GI bleeding and wound healing complications after surgery of liver metastases
General safety
Overall Response Rate ORR
Recurrence Free Survival RFS
Overall Survival OS
STUDY DURATION Recruitment is planned for 12 months Patients will be treated for 6 cycles XELOX and 5 cycles Bevacizumab Surgery will be performed 2 weeks after the last Capecitabine administration allowing a time window of 5 weeks between the last Bevacizumab administration and surgery
Therapy with 6 cycles of XELOX and Bevacizumab will be restarted 4-5 weeks after surgery
With a Follow up period of 2 years after the last enrolled patient in order to assess RFS and OS the trial will last for approx 3 years
NUMBER OF CENTRES Four centres with a high level of experience in the surgery of liver metastases are planned to participate in this study
SELECTION CRITERIA
Total Number of Patients and Target Population The planned total sample size for this study is 43 patients Patients with potentially resectable metastatic colorectal cancer previously untreated for metastatic disease will be enrolled in this trial
STUDY OBJECTIVES
Primary Objective The primary objective of this study is the Resectability R0 rate after neoadjuvant Bevacizumab in potentially resectable mCRC
Secondary Objectives The secondary objectives of this study include
Feasibility with regards to GI bleeding and wound healing complications after surgery of liver metastases
General safety
Overall Response Rate ORR
Recurrence Free Survival RFS
Overall Survival OS
STUDY DURATION Recruitment is planned for 12 months Patients will be treated for 6 cycles XELOX and 5 cycles Bevacizumab Surgery will be performed 2 weeks after the last Capecitabine administration allowing a time window of 5 weeks between the last Bevacizumab administration and surgery
Therapy with 6 cycles of XELOX and Bevacizumab will be restarted 4-5 weeks after surgery
With a Follow up period of 2 years after the last enrolled patient in order to assess RFS and OS the trial will last for approx 3 years
NUMBER OF CENTRES Four centres with a high level of experience in the surgery of liver metastases are planned to participate in this study
SELECTION CRITERIA
Total Number of Patients and Target Population The planned total sample size for this study is 43 patients Patients with potentially resectable metastatic colorectal cancer previously untreated for metastatic disease will be enrolled in this trial
Detailed Description:
Major attempt is being given to the potential of curing patients with metastatic colorectal cancer due to the recognition of dramatic change in survival figures achieved in palliative chemotherapy combination treatment protocols Achieving resectablity rates in previously unresectable patients has been defined as study endpoint among other well known primary and secondary objectives Curing metastatic colorectal cancer is most likely in resectable patients and therefore the logical next step after completion of chemotherapy combination studies eg EORTC 40983 is the addition of targeted agents Bevacizumab has the most valid data of improving outcome figures and was therefore chosen as additional agent Safety of the combination with Xelox was demonstrated in our pilot trial Gruenberger JCO 2006 ASCO 2006 WCGC 2006 ESMO 2006 consequently response rate and resection rate will be the primary endpoints in this trial
STUDY OBJECTIVES
Primary Objective The primary objective of this study is the Resectability R0 rate after neoadjuvant Bevacizumab in potentially resectable mCRC
Secondary Objectives The secondary objectives of this study include
Feasibility with regards to GI bleeding and wound healing complications after surgery of liver metastases
General safety
Overall Response Rate ORR
Recurrence Free Survival RFS
Overall Survival OS
STUDY DURATION Recruitment is planned for 12 months Patients will be treated for 6 cycles XELOX and 5 cycles Bevacizumab Surgery will be performed 2 weeks after the last Capecitabine administration allowing a time window of 5 weeks between the last Bevacizumab administration and surgery
Therapy with 6 cycles of XELOX and Bevacizumab will be restarted 4-5 weeks after surgery
With a Follow up period of 2 years after the last enrolled patient in order to assess RFS and OS the trial will last for approx 3 years
NUMBER OF CENTRES Four centres with a high level of experience in the surgery of liver metastases are planned to participate in this study
SELECTION CRITERIA
Total Number of Patients and Target Population The planned total sample size for this study is 40 patients Patients with potentially resectable metastatic colorectal cancer previously untreated for metastatic disease will be enrolled in this trial
STUDY DESIGN
Design This is a single arm multicenter Phase III trial to evaluate the Resectability R0 rate after neoadjuvant Bevacizumab in combination with a biweekly regime of capecitabine plus oxaliplatin XELOX in potentially resectable mCRC
The pre-operative treatment phase consists of 6 cycles XELOX and 5 cycles Bevacizumab The cycle duration is 2 weeks
Surgery will be performed 2 weeks after the last administration of Capecitabine allowing a time window of 5 weeks between the last dose of Bevacizumab and surgery
The post-operative treatment phase consists of 6 cycles XELOX Bevacizumab and will be re-started 4-5 weeks after surgery
Patients will be further followed for tumour progression and survival for a further 2 years after the last patient has been enrolled in this trial end of the study follow up
Schedule of Assessment and Study Procedures Study assessments and procedures will be performed as shown in Table 1 and 2 Screening and Baseline Written informed consent must be obtained prior to the patient undergoing any study-specific procedures
1 Tumor assessments abdominal and pelvic CT MRI and chest CT MRI may be obtained up to 4 weeks prior to enrollment
2 Assessments to be made up to 14 days before enrollment include demographic data medical history cancertreatment history concomitant diseasetreatment physical examination including basic neurologic exam by investigator electrocardiogram ECG and CEA CA 19-9 determination
3 Assessments to be made within 7 days before enrollment height weight vital signs body temperature blood pressure and pulseheart rate ECOG Performance Status hematology blood chemistry including creatinine clearance calculation INR aPTT serum pregnancy test for all women less than 2 years amenorrheic dipstick urinalysis for proteinuria and 24-hour urine collection for determination of total protein if necessary
4 Urine pregnancy test is required prior to first administration of study treatment if more than 7 days have elapsed from baseline serum pregnancy test
If a Central Venous Access Device CVAD is required at least a 2-day interval between placement of a central line and first bevacizumab administration is recommended
Treatment Phase pre- and post-operative Standard Clinical Assessments
Physical examination including basic neurologic exam by investigator
ECOG performance status see Appendix 4
Vital signs weight body temperature blood pressure pulse heart rate
On each scheduled visit patients will be assessed for adverse events grading by the common terminology criteria for adverse events CTCAE version 30
Laboratory Assessments
The following laboratory tests are to be done
White blood cell count with differentials lymphocytes neutrophils red blood cell count hemoglobin hematocrit and platelet count
Bilirubin total and direct ASAT ALAT alkaline phosphatase albumin LDH
Serum creatinine
Glucose
Electrolytes sodium potassium
Calcium
INR for patients receiving oral anticoagulant treatment
CEA CA 19-9
Urinalysis dip stick test for protein is to be performed before each administration of bevacizumab
Serum pregnancy tests if clinically indicated
Surgery and Control Visits after Surgery
The first control visit should be performed 10 days after surgery and should include the following assessments
ECOG performance status
Vital signs weight body temperature blood pressure pulse heart rate
Haematology Blood chemistry and Coagulation
Adverse events grading by the common terminology criteria for adverse events CTCAE version 30 with special regard to wound healing
The second control visit will be performed 21 days after surgery and should include the same assessments as on the first control visit with the addition of
Physical examination
Electrocardiogram ECG
Tumour Assessment
Final Visit End of treatment safety visit to be performed 28 days after the last drug administration
Follow up Phase and Termination of Study Progression Free Survival Status and Survival status should be assessed every 3 months for a maximum of 2 years
STUDY MEDICATION
Dose Schedule and Administration Bevacizumab Bevacizumab will be given at 5 mgkg on d1 every two weeks for 5 consecutive cycles The 6th cycle will be XELOX without Bevacizumab allowing for a time window between last administration of Bevacizumab and surgery of 5 weeks
The time window between surgery and re-start of treatment will be at least 4 weeks and wound healing must be completed Bevacizumab will then be given at 5 mgkg on d1 every two weeks for 6 consecutive cycles in combination with XELOX
Bevacizumab doses will be calculated for each patient in milligrams per kilogram The patients actual weight from the screening visit will be the reference weight throughout the study ie patients will receive the same dose at each treatment Doses of Bevacizumab will be recalculated for patients who experience more than 10 change in body weight from baseline during the treatment period
All patients will receive an infusion of study drug in a total volume of 100 mL of 09 Sodium Chloride Injection USP Bevacizumab infusions should not be administered or mixed with dextrose or glucose solutions
The initial study drug dose will be delivered over 90 minutes as a continuous IV infusion If the first infusion is tolerated without infusion associated adverse events the second infusion may be delivered over 60 minutes If the 60 minute infusion is tolerated all subsequent infusions may be delivered over 30 minutes If a patient experiences infusion associated adverse events with the 60 minute infusion all subsequent doses will be given over 90 minutes If a patient experiences infusion associated adverse events with the 30 minute infusion all subsequent doses will be given over 60 minutes
Should extravasation of the study drug infusion occur the following steps are to be taken
1 Discontinue the IV
2 If a significant volume of the study drug infusion remains restart the IV at a more proximal site in the same limb
3 Treat the infiltration according to institutional guidelines for infiltration of a noncaustic agent
In the pre-surgery phase Bevacizumab will be obtained locally by prescription After surgery Bevacizumab will be supplied as glass vials with 4-mL fill containing 100 mg 25 mgmL or with 16-mL fill containing 400 mg 25 mgmL Vials contain no preservative and are for single use only
Oxaliplatin Liquid Oxaliplatin will be given at 85 mgm2 on d1 every two weeks for 6 consecutive cycles before and after surgery
Liquid Oxaliplatin dose will be calculated using the body surface area BSA of the patient see Appendix 2 The dose of oxaliplatin administered should be as close as possible to the calculated dose
Liquid Oxaliplatin administration does not require hyperhydration In the event of extravasation administration must be discontinued immediately
For nausea and vomiting 5-HT3 antagonists with or without dexamethasone are strongly recommended for oxaliplatin-based chemotherapy
Liquid Oxaliplatin must be infused either by peripheral vein or central venous line over 2 hours The infusion line must be adequately flushed with 5 dextrose solution D5W between oxaliplatin infusion and the administration of any other drug
Liquid Oxaliplatin Eloxatin will be obtained locally by prescription
Capecitabine The dose of Capecitabine is 1500 mgm2 twice daily from the evening of d1 until the morning of d8 followed by 1 week rest period One treatment cycle consists of 2 weeks Capecitabine will be given for 6 consecutive cycles before and after surgery
The appropriate daily dose of capecitabine is identified by determination of the Body Surface Area see Appendix 2 and 3
Capecitabine is to be administered orally within 30 minutes after the end of a meal breakfast dinner Tablets should be swallowed with approximately 200 mL water not fruit juices The first dose of each cycle will be administered as the evening dose on day 1 and the last dose of each cycle is scheduled the morning of day 8 followed by a 7 day rest period
Capecitabine Xeloda will be obtained locally by prescription
Study Treatment Duration In the pre-operative treatment phase 6 cycles of XELOX and 5 cycles of Bevacizumab will be administered resulting in a total treatment duration of 12 weeks
Surgery will be performed 2 weeks after the last administration of Capecitabine
Post-operative treatment consists of 6 cycles XELOX Bevacizumab and will re-start 4-5 weeks after surgery
STUDY OBJECTIVES
Primary Objective The primary objective of this study is the Resectability R0 rate after neoadjuvant Bevacizumab in potentially resectable mCRC
Secondary Objectives The secondary objectives of this study include
Feasibility with regards to GI bleeding and wound healing complications after surgery of liver metastases
General safety
Overall Response Rate ORR
Recurrence Free Survival RFS
Overall Survival OS
STUDY DURATION Recruitment is planned for 12 months Patients will be treated for 6 cycles XELOX and 5 cycles Bevacizumab Surgery will be performed 2 weeks after the last Capecitabine administration allowing a time window of 5 weeks between the last Bevacizumab administration and surgery
Therapy with 6 cycles of XELOX and Bevacizumab will be restarted 4-5 weeks after surgery
With a Follow up period of 2 years after the last enrolled patient in order to assess RFS and OS the trial will last for approx 3 years
NUMBER OF CENTRES Four centres with a high level of experience in the surgery of liver metastases are planned to participate in this study
SELECTION CRITERIA
Total Number of Patients and Target Population The planned total sample size for this study is 40 patients Patients with potentially resectable metastatic colorectal cancer previously untreated for metastatic disease will be enrolled in this trial
STUDY DESIGN
Design This is a single arm multicenter Phase III trial to evaluate the Resectability R0 rate after neoadjuvant Bevacizumab in combination with a biweekly regime of capecitabine plus oxaliplatin XELOX in potentially resectable mCRC
The pre-operative treatment phase consists of 6 cycles XELOX and 5 cycles Bevacizumab The cycle duration is 2 weeks
Surgery will be performed 2 weeks after the last administration of Capecitabine allowing a time window of 5 weeks between the last dose of Bevacizumab and surgery
The post-operative treatment phase consists of 6 cycles XELOX Bevacizumab and will be re-started 4-5 weeks after surgery
Patients will be further followed for tumour progression and survival for a further 2 years after the last patient has been enrolled in this trial end of the study follow up
Schedule of Assessment and Study Procedures Study assessments and procedures will be performed as shown in Table 1 and 2 Screening and Baseline Written informed consent must be obtained prior to the patient undergoing any study-specific procedures
1 Tumor assessments abdominal and pelvic CT MRI and chest CT MRI may be obtained up to 4 weeks prior to enrollment
2 Assessments to be made up to 14 days before enrollment include demographic data medical history cancertreatment history concomitant diseasetreatment physical examination including basic neurologic exam by investigator electrocardiogram ECG and CEA CA 19-9 determination
3 Assessments to be made within 7 days before enrollment height weight vital signs body temperature blood pressure and pulseheart rate ECOG Performance Status hematology blood chemistry including creatinine clearance calculation INR aPTT serum pregnancy test for all women less than 2 years amenorrheic dipstick urinalysis for proteinuria and 24-hour urine collection for determination of total protein if necessary
4 Urine pregnancy test is required prior to first administration of study treatment if more than 7 days have elapsed from baseline serum pregnancy test
If a Central Venous Access Device CVAD is required at least a 2-day interval between placement of a central line and first bevacizumab administration is recommended
Treatment Phase pre- and post-operative Standard Clinical Assessments
Physical examination including basic neurologic exam by investigator
ECOG performance status see Appendix 4
Vital signs weight body temperature blood pressure pulse heart rate
On each scheduled visit patients will be assessed for adverse events grading by the common terminology criteria for adverse events CTCAE version 30
Laboratory Assessments
The following laboratory tests are to be done
White blood cell count with differentials lymphocytes neutrophils red blood cell count hemoglobin hematocrit and platelet count
Bilirubin total and direct ASAT ALAT alkaline phosphatase albumin LDH
Serum creatinine
Glucose
Electrolytes sodium potassium
Calcium
INR for patients receiving oral anticoagulant treatment
CEA CA 19-9
Urinalysis dip stick test for protein is to be performed before each administration of bevacizumab
Serum pregnancy tests if clinically indicated
Surgery and Control Visits after Surgery
The first control visit should be performed 10 days after surgery and should include the following assessments
ECOG performance status
Vital signs weight body temperature blood pressure pulse heart rate
Haematology Blood chemistry and Coagulation
Adverse events grading by the common terminology criteria for adverse events CTCAE version 30 with special regard to wound healing
The second control visit will be performed 21 days after surgery and should include the same assessments as on the first control visit with the addition of
Physical examination
Electrocardiogram ECG
Tumour Assessment
Final Visit End of treatment safety visit to be performed 28 days after the last drug administration
Follow up Phase and Termination of Study Progression Free Survival Status and Survival status should be assessed every 3 months for a maximum of 2 years
STUDY MEDICATION
Dose Schedule and Administration Bevacizumab Bevacizumab will be given at 5 mgkg on d1 every two weeks for 5 consecutive cycles The 6th cycle will be XELOX without Bevacizumab allowing for a time window between last administration of Bevacizumab and surgery of 5 weeks
The time window between surgery and re-start of treatment will be at least 4 weeks and wound healing must be completed Bevacizumab will then be given at 5 mgkg on d1 every two weeks for 6 consecutive cycles in combination with XELOX
Bevacizumab doses will be calculated for each patient in milligrams per kilogram The patients actual weight from the screening visit will be the reference weight throughout the study ie patients will receive the same dose at each treatment Doses of Bevacizumab will be recalculated for patients who experience more than 10 change in body weight from baseline during the treatment period
All patients will receive an infusion of study drug in a total volume of 100 mL of 09 Sodium Chloride Injection USP Bevacizumab infusions should not be administered or mixed with dextrose or glucose solutions
The initial study drug dose will be delivered over 90 minutes as a continuous IV infusion If the first infusion is tolerated without infusion associated adverse events the second infusion may be delivered over 60 minutes If the 60 minute infusion is tolerated all subsequent infusions may be delivered over 30 minutes If a patient experiences infusion associated adverse events with the 60 minute infusion all subsequent doses will be given over 90 minutes If a patient experiences infusion associated adverse events with the 30 minute infusion all subsequent doses will be given over 60 minutes
Should extravasation of the study drug infusion occur the following steps are to be taken
1 Discontinue the IV
2 If a significant volume of the study drug infusion remains restart the IV at a more proximal site in the same limb
3 Treat the infiltration according to institutional guidelines for infiltration of a noncaustic agent
In the pre-surgery phase Bevacizumab will be obtained locally by prescription After surgery Bevacizumab will be supplied as glass vials with 4-mL fill containing 100 mg 25 mgmL or with 16-mL fill containing 400 mg 25 mgmL Vials contain no preservative and are for single use only
Oxaliplatin Liquid Oxaliplatin will be given at 85 mgm2 on d1 every two weeks for 6 consecutive cycles before and after surgery
Liquid Oxaliplatin dose will be calculated using the body surface area BSA of the patient see Appendix 2 The dose of oxaliplatin administered should be as close as possible to the calculated dose
Liquid Oxaliplatin administration does not require hyperhydration In the event of extravasation administration must be discontinued immediately
For nausea and vomiting 5-HT3 antagonists with or without dexamethasone are strongly recommended for oxaliplatin-based chemotherapy
Liquid Oxaliplatin must be infused either by peripheral vein or central venous line over 2 hours The infusion line must be adequately flushed with 5 dextrose solution D5W between oxaliplatin infusion and the administration of any other drug
Liquid Oxaliplatin Eloxatin will be obtained locally by prescription
Capecitabine The dose of Capecitabine is 1500 mgm2 twice daily from the evening of d1 until the morning of d8 followed by 1 week rest period One treatment cycle consists of 2 weeks Capecitabine will be given for 6 consecutive cycles before and after surgery
The appropriate daily dose of capecitabine is identified by determination of the Body Surface Area see Appendix 2 and 3
Capecitabine is to be administered orally within 30 minutes after the end of a meal breakfast dinner Tablets should be swallowed with approximately 200 mL water not fruit juices The first dose of each cycle will be administered as the evening dose on day 1 and the last dose of each cycle is scheduled the morning of day 8 followed by a 7 day rest period
Capecitabine Xeloda will be obtained locally by prescription
Study Treatment Duration In the pre-operative treatment phase 6 cycles of XELOX and 5 cycles of Bevacizumab will be administered resulting in a total treatment duration of 12 weeks
Surgery will be performed 2 weeks after the last administration of Capecitabine
Post-operative treatment consists of 6 cycles XELOX Bevacizumab and will re-start 4-5 weeks after surgery
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None