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Optimization of Bevacizumab Scheduling With Chemotherapy for Metastatic Colorectal Cancer (OBELICS)

Primary Purpose

Colorectal Cancer

Status
Completed
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Bevacizumab
Oxaliplatin
levo-folinic acid
5-fluorouracil
Capecitabine
Sponsored by
National Cancer Institute, Naples
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring metastatic, stage IV

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Istituto Nazionale Tumori Fondazione G. Pascale

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

bevacizumab before chemotherapy

bevacizumab with chemotherapy

Arm Description

Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)

Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Disease Control Rate
Disease control rate was calculated by adding complete and partial responses and stable disease.
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.
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.
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.

Full Information

First Posted
October 29, 2012
Last Updated
April 11, 2023
Sponsor
National Cancer Institute, Naples
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1. Study Identification

Unique Protocol Identification Number
NCT01718873
Brief Title
Optimization of Bevacizumab Scheduling With Chemotherapy for Metastatic Colorectal Cancer
Acronym
OBELICS
Official Title
Randomized Phase 3 Study on the Optimization of Bevacizumab With mFOLFOX/mOXXEL in the Treatment of Patients With Metastatic Colorectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
May 2012 (Actual)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute, Naples

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
metastatic, stage IV

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
230 (Actual)

8. Arms, Groups, and Interventions

Arm Title
bevacizumab before chemotherapy
Arm Type
Experimental
Arm Description
Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
Arm Title
bevacizumab with chemotherapy
Arm Type
Active Comparator
Arm Description
Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Other Intervention Name(s)
Eloxatin
Intervention Description
85mg/m2 IV every 2 weeks for up to 24 weeks
Intervention Type
Drug
Intervention Name(s)
levo-folinic acid
Other Intervention Name(s)
Lederfolin
Intervention Description
200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks
Intervention Type
Drug
Intervention Name(s)
5-fluorouracil
Other Intervention Name(s)
Fluorouracil
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Capecitabine
Other Intervention Name(s)
Xeloda
Intervention Description
1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)
Primary Outcome Measure Information:
Title
Objective Response Rate
Description
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.
Secondary Outcome Measure Information:
Title
Disease Control Rate
Description
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
Title
Overall Survival
Description
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
Title
Progression-free Survival (PFS)
Description
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
Title
Toxic Effects
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonio Avallone, M.D.
Organizational Affiliation
National Cancer Institute, Naples
Official's Role
Principal Investigator
Facility Information:
Facility Name
Istituto Nazionale Tumori Fondazione G. Pascale
City
Napoli
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
34309665
Citation
Avallone A, Piccirillo MC, Nasti G, Rosati G, Carlomagno C, Di Gennaro E, Romano C, Tatangelo F, Granata V, Cassata A, Silvestro L, De Stefano A, Aloj L, Vicario V, Nappi A, Leone A, Bilancia D, Arenare L, Petrillo A, Lastoria S, Gallo C, Botti G, Delrio P, Izzo F, Perrone F, Budillon A. Effect of Bevacizumab in Combination With Standard Oxaliplatin-Based Regimens in Patients With Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2021 Jul 1;4(7):e2118475. doi: 10.1001/jamanetworkopen.2021.18475.
Results Reference
derived
PubMed Identifier
26857924
Citation
Avallone A, Piccirillo MC, Aloj L, Nasti G, Delrio P, Izzo F, Di Gennaro E, Tatangelo F, Granata V, Cavalcanti E, Maiolino P, Bianco F, Aprea P, De Bellis M, Pecori B, Rosati G, Carlomagno C, Bertolini A, Gallo C, Romano C, Leone A, Caraco C, de Lutio di Castelguidone E, Daniele G, Catalano O, Botti G, Petrillo A, Romano GM, Iaffaioli VR, Lastoria S, Perrone F, Budillon A. A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme). BMC Cancer. 2016 Feb 8;16:69. doi: 10.1186/s12885-016-2102-y.
Results Reference
derived

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Optimization of Bevacizumab Scheduling With Chemotherapy for Metastatic Colorectal Cancer

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