Optimization of Bevacizumab Scheduling With Chemotherapy for Metastatic Colorectal Cancer

Phase 3

Completed

• Conditions: Colorectal Cancer
• Interventions: Drug: Bevacizumab; Drug: Oxaliplatin; Drug: levo-folinic acid; Drug: 5-fluorouracil; Drug: Capecitabine

• Registration Number: NCT01718873
• Lead Sponsor: National Cancer Institute, Naples

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.

Study Timeline

• Study Start: 2012-05
• Study First Submitted: 2012-10-29
• Study First Submitted QC: 2012-10-29
• Study First Posted: 2012-10-31
• Primary Completion: 2015-12
• Study Completion: 2019-12
• Results First Submitted: 2021-08-20
• Status Verified: 2021-10
• Results First Submitted QC: 2023-04-11
• Last Update Submitted: 2023-04-11
• Results First Posted: 2023-04-12
• Last Update Posted: 2023-04-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 230

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
bevacizumab before chemotherapy	levo-folinic acid	Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab with chemotherapy	levo-folinic acid	Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab before chemotherapy	Bevacizumab	Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab before chemotherapy	5-fluorouracil	Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab before chemotherapy	Oxaliplatin	Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab with chemotherapy	Bevacizumab	Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab with chemotherapy	5-fluorouracil	Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab before chemotherapy	Capecitabine	Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab with chemotherapy	Oxaliplatin	Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
bevacizumab with chemotherapy	Capecitabine	Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (1)

Istituto Nazionale Tumori Fondazione G. Pascale; 🇮🇹 Napoli, Italy