Colorectal Cancer
Conditions
Keywords
metastatic, stage IV
Brief summary
The purpose of this study is to evaluate if giving bevacizumab prior to chemotherapy compared to giving bevacizumab at the same time as chemotherapy improves patient overall response to treatment.
Detailed description
OBELICS is a two-arm phase 3 trial comparing in mCRC patients (1:1): concurrent administration of bevacizumab in combination with modified FOLFOX-6 regimen (mFOLFOX-6) or modified OXXEL regimen (mOXXEL), in which bevacizumab is administered the same day as oxaliplatin, (standard arm); and sequential administration of bevacizumab with the same chemotherapeutic regimens, in which bevacizumab is administered 4 days before oxaliplatin at each cycle (experimental arm) Oxaliplatin regimen (mFOLFOX/mOXXEL) is chosen according to local clinical practice at the beginning of the study.
Interventions
DRUGBevacizumab
5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.
DRUGOxaliplatin
85mg/m2 IV every 2 weeks for up to 24 weeks
DRUGlevo-folinic acid
200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks
DRUG5-fluorouracil
400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)
DRUGCapecitabine
1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)
Sponsors
National Cancer Institute, Naples
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Histological diagnosis of colorectal adenoma carcinoma * Stage IV disease * Presence of at least one measurable target lesion (according to RECIST), and not previously radiated. * Age ≥ 18 e ≤ 75 years * ECOG Performance status 0-1 * Life expectancy \>3 months * Adequate recovery from surgery, with at least 28 days from surgery to date of pre-study biopsy. * Adequate contraception for male and female patients of child bearing potential * informed consent
Exclusion criteria
* More than one previous line of therapy for metastatic disease * Prior treatment with bevacizumab or oxaliplatin (previous treatment with irinotecan,, cetuximab, fluoropyrimidine, folic acid are permitted) * Primary tumor that is stenosing and/or that infiltrates the entire thickness of the intestinal wall * Regular use of NSAIDs or aspirin * Bleeding disorders or coagulopathy * Concurrent anticoagulant therapy * Suspected or cerebral metastases (to verify in the presence of symptoms) * Neutrophils \< 2000 / mm3, platelets \< 100,000 / mm3, hemoglobin \< 9g/dl * Creatinine \> 1.5 times the upper normal limit * GOT and/or GPT \> 2.5 times the upper normal limit, bilirubin \> 1.5 times the upper normal limit in absence of liver metastases * GOT and/or GPT \> 5 times the upper normal limit, bilirubin \> 3 times the upper normal limit in presence of liver metastases * Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal and squamous cell carcinoma or cervical cancer in situ * Congestive heart failure, ischemic coronary events within past 12 months, uncontrolled cardiac arrhythmia * Uncontrolled hypertension * Active or uncontrolled infection * Any concomitant condition that, in the investigator's opinion, would contraindicate the use of any of the study drugs * Pregnancy or lactation * Central nervous system disorders or peripheral neuropathy \> grade 1 (CTCAE v. 4.0) * Inability to comply with follow up procedures of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Objective response was assessed by computed tomographic scan or other appropriate imaging at weeks 12 and 24 from randomization, and every 3 months thereafter, assessed up to 90 months. | Objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, was the primary end point and was defined as the number of complete plus partial responses divided by the number of enrolled patients. Per RECIST v 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate | At weeks 12 and 24 from randomization and every 3 months thereafter, assessed up to 90 months | Disease control rate was calculated by adding complete and partial responses and stable disease. |
| Overall Survival | assessed up to 90 months | Overall survival was defined as the time from randomization to the date of death. Patients alive at the time of the final analysis were censored on the date of the last follow-up information available. |
| Progression-free Survival (PFS) | assessed up to 90 months | Progression-free survival was defined as the time from randomization to the date of progression or death, whichever occurred first. Patients without progression were censored on the date of the last follow-up visit. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), 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. |
| Toxic Effects | up to 4 weeks after the end of the treatment | Toxic effects were scored according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. For the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 scale score range from 1 to 4. A high score, that is 3 and 4, represents a high level of toxicity, whereas the minimum values, that is 1 and 2, represents a mild/modest level of toxicity. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab Before Chemotherapy Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule) | 115 |
| Bevacizumab With Chemotherapy Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule) | 115 |
| Total | 230 |
Baseline characteristics
| Characteristic | Bevacizumab With Chemotherapy | Total | Bevacizumab Before Chemotherapy |
|---|---|---|---|
| Age, Continuous | 63 years | 62.3 years | 61 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 115 Participants | 230 Participants | 115 Participants |
| Sex: Female, Male Female | 48 Participants | 94 Participants | 46 Participants |
| Sex: Female, Male Male | 67 Participants | 136 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 115 | 2 / 115 |
| other Total, other adverse events | 108 / 115 | 113 / 115 |
| serious Total, serious adverse events | 65 / 115 | 75 / 115 |
Outcome results
Primary
Objective Response Rate
Objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, was the primary end point and was defined as the number of complete plus partial responses divided by the number of enrolled patients. Per RECIST v 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Objective response was assessed by computed tomographic scan or other appropriate imaging at weeks 12 and 24 from randomization, and every 3 months thereafter, assessed up to 90 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab Before Chemotherapy | Objective Response Rate | 65 participants |
| Bevacizumab With Chemotherapy | Objective Response Rate | 66 participants |
Secondary
Disease Control Rate
Disease control rate was calculated by adding complete and partial responses and stable disease.
Time frame: At weeks 12 and 24 from randomization and every 3 months thereafter, assessed up to 90 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab Before Chemotherapy | Disease Control Rate | 107 Participants |
| Bevacizumab With Chemotherapy | Disease Control Rate | 103 Participants |
Secondary
Overall Survival
Overall survival was defined as the time from randomization to the date of death. Patients alive at the time of the final analysis were censored on the date of the last follow-up information available.
Time frame: assessed up to 90 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Before Chemotherapy | Overall Survival | 29.8 months |
| Bevacizumab With Chemotherapy | Overall Survival | 24.1 months |
Secondary
Progression-free Survival (PFS)
Progression-free survival was defined as the time from randomization to the date of progression or death, whichever occurred first. Patients without progression were censored on the date of the last follow-up visit. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), 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.
Time frame: assessed up to 90 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Before Chemotherapy | Progression-free Survival (PFS) | 11.7 months |
| Bevacizumab With Chemotherapy | Progression-free Survival (PFS) | 10.5 months |
Secondary
Toxic Effects
Toxic effects were scored according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. For the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 scale score range from 1 to 4. A high score, that is 3 and 4, represents a high level of toxicity, whereas the minimum values, that is 1 and 2, represents a mild/modest level of toxicity.
Time frame: up to 4 weeks after the end of the treatment
Population: any grade of toxic effects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab Before Chemotherapy | Toxic Effects | 108 Participants |
| Bevacizumab With Chemotherapy | Toxic Effects | 113 Participants |