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Digestive System Diseases

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

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Digestive System Neoplasms

Gastrointestinal Diseases

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Antineoplastic Agents

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Micronutrients

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Bevacizumab

Irinotecan

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Fluorouracil

Oxaliplatin

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Levoleucovorin

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Folinic Acid

Folate

Vitamin B9

5-FU

3200mg/m2 46-hour continuous iv infusion, day 1 every 2 weeks

2400mg/m2 46-hour continuous iv infusion, day 1 every 2 weeks

165mg/m2 1-hour iv infusion, day 1 every 2 weeks

400mg/m2 2-hour iv infusion, day 1 every 2 weeks

200mg/m2 2-hour iv infusion, day 1 every 2 weeks

85mg/m2 2-hour iv infusion, day 1 every 2 weeks

bevacizumab [Avastin]

Clinical Trials

This 2 arm study will compare the resection rate of liver metastases and safety of surgery in patients with metastatic colorectal cancer and primarily unresectable liver metastases receiving treatment with Avastin in combination with 5-FU, leucovorin and oxaliplatin with irinotecan (FOLFOXIRI) or without irinotecan (mFOLFOX-6) as first line treatment. Patients will be randomized to receive Avastin (5mg/kg iv every 2 weeks) in combination with each of these two standard neoadjuvant chemotherapy regimens. The anticipated time on study treatment is until surgery, disease progression, unacceptable toxicity or patient refusal, and the target sample size is \<100 individuals.

A Study of Avastin (Bevacizumab) in Combination With mFOLFOX-6 or FOLFOXIRI in Patients With Metastatic Colorectal Cancer.

A Multicentre Randomised Phase II Study to Assess the Safety and Resectability in Patients With Initially Unresectable Liver Metastases Secondary to Colorectal Cancer Receiving First-line Treatment Either With mFOLFOX-6 Plus Bevacizumab or FOLFOXIRI Plus Bevacizumab (OLIVIA)

Following resective surgery, participants were evaluated for complete resection (R0) or the presence of microscopic (R1) or macroscopic (R2) residual tumor. The percentage of participants within each residual tumor classification was calculated as \[number of participants with R0, R1, and/or R2 divided by the total number of participants\] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.

Time to resection was defined as the time from randomization to the date of first resective surgery. For participants who did not undergo resective surgery, time to resection was censored at Day 1. Time to resection was estimated by Kaplan-Meier analysis.

At the time of resective surgery, participants were evaluated for histopathological response as defined through pathologist review of the resected metastatic lesions, including assessment of margin status and tumor cell viability. Histopathological response classification was based upon the percentage of viable tumor cells, where 'Complete response' was considered for those with 0 percent (%) viable tumor cells, 'Major response' for those with 1% to 49% viable tumor cells, 'Minor response' for 50% to 99% viable tumor cells, and 'No response' for 100% viable tumor cells. The response could not be determined in some cases and was documented as 'Unknown.' The percentage of participants within each response category was calculated as \[number of participants with a given response divided by the number of participants who completed the assessment\] multiplied by 100.

At the time of resective surgery, participants were evaluated for histopathological response as defined through pathologist review of the resected metastatic lesions, including assessment of margin status and tumor cell viability. Histopathological response classification was based upon the percentage of viable tumor cells, as described previously. The collective percentage of participants assessed as having a complete or major response was calculated as \[number of participants with complete or major response divided by the number of participants who completed the assessment\] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.

Among participants with curative resection (complete resection \[R0\] or microscopic residual tumor \[R1\]), relapse was defined as the first new occurrence of cancer or death. The percentage of participants who experienced relapse was calculated as \[number of participants with a relapse event divided by the number of participants initially classified as R0 or R1 following resective surgery\] multiplied by 100.

RFS was defined as the time from curative resection (complete resection \[R0\] or microscopic residual tumor \[R1\]) to the date of first diagnosis of relapse. For participants with curative resection and without relapse, RFS was censored at the last known relapse-free assessment. RFS was estimated by Kaplan-Meier analysis.

PD was defined, using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. The percentage of participants experiencing PD or death was calculated as \[number of participants with event divided by the number of participants analyzed\] multiplied by 100.

PFS was defined, using RECIST version 1.0, as the time from randomization to the date of first documented PD or death from any cause. PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. For participants without documented PD or death, PFS was censored at the time of last tumor assessment. PFS was estimated by Kaplan-Meier analysis.

OS was defined as the time from randomization to death from any cause. For participants without an event of death, OS was censored at the last-known alive date. OS was estimated by Kaplan-Meier analysis.

Using RECIST version 1.0, participants were considered to have achieved CR upon the disappearance of all target and non-target lesions. Participants who achieved PR demonstrated at least a 30% decrease in the sum of the largest diameter of target lesions, taking as reference the Screening sum largest diameter. Responses were confirmed by repeat assessments no less than 4 weeks after criteria for response were first met. The collective percentage of participants with confirmed best overall response of CR or PR was calculated as \[number of participants meeting RECIST criteria for CR or PR divided by the number of participants analyzed\] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.

Time to response according to RECIST version 1.0 was defined as the time from randomization to the date of first documented CR or PR. Participants were considered to have achieved CR upon the disappearance of all target and non-target lesions. Participants who achieved PR demonstrated at least a 30% decrease in the sum of the largest diameter of target lesions, taking as reference the Screening sum largest diameter. Responses were confirmed by repeat assessments no less than 4 weeks after criteria for response were first met. For participants who did not complete a confirmatory tumor assessment, time to response was censored at the date of last tumor assessment, or if unavailable, at the date of first dose. Time to response was estimated by Kaplan-Meier analysis.

Complications related to the first resective surgery were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0, and classified according to severity. The NCI-CTCAE severity classification criteria are as follows: Grade 5 equals (=) resulting in death; Grade 4 = life-threatening; Grade 3 = severe; Grade 2 = moderate; and Grade 1 = mild. The percentage of participants experiencing a given adverse event (AE) by severity grade was calculated as \[number of participants with an AE divided by the number of participants who underwent first resective surgery\] multiplied by 100.

Complications related to the second resective surgery were evaluated using the NCI-CTCAE version 3.0, and classified according to severity. The NCI-CTCAE severity classification criteria are as follows: Grade 5 = resulting in death; Grade 4 = life-threatening; Grade 3 = severe; Grade 2 = moderate; and Grade 1 = mild. The percentage of participants experiencing a given AE by severity grade was calculated as \[number of participants with an AE divided by the number of participants who underwent second resective surgery\] multiplied by 100.

Hoffmann-La Roche

Safety Population: All participants who received at least one dose of trial medication, whether prematurely withdrawn or not.

Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

Bevacizumab + mFOLFOX-6

Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

Bevacizumab + FOLFOXIRI

Total

Age, Continuous

Gender

Intent-to-Treat (ITT) Population: All randomized participants. Participants were analyzed according to which treatment group they were randomized, regardless of the treatment actually received.

Medical Communications

Difference between groups in the collective percentage of participants with R0, R1, or R2.

R0, R1, or R2

R0 or R1

Percentage of Participants With Complete Resection or Residual (Microscopic or Macroscopic) Tumor

Time to Resection

Complete response

Major response

Minor response

No response

Unknown

ITT Population; only participants with a histopathological assessment after the first resective surgery were included in the analysis.

Percentage of Participants With Histopathological Response

Difference between groups in the collective percentage of participants with complete or major histopathological response.

Percentage of Participants With Complete or Major Histopathological Response

ITT Population; only participants with a residual tumor classification of R0 or R1 after first resection were included in the analysis.

Percentage of Participants Experiencing Relapse Following Curative Resection

Relapse-Free Survival (RFS)

Percentage of Participants Experiencing Death or Disease Progression

Progression-Free Survival (PFS)

Percentage of Participants Who Died

Overall Survival (OS)

Difference between groups in the collective percentage of participants with confirmed best overall response of CR or PR.

Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.0

Time to Response

Any complication, Total

Any complication, Grade 1

Any complication, Grade 2

Any complication, Grade 3

Any complication, Grade 4

Any complication, Grade 5

Bleeding, Total

Bleeding, Grade 1

Bleeding, Grade 2

Bleeding, Grade 3

Cardiovascular, Total

Cardiovascular, Grade 2

Cardiovascular, Grade 3

Cardiovascular, Grade 4

Infections, Total

Infections, Grade 1

Infections, Grade 2

Infections, Grade 3

Infections, Grade 4

Liver insufficiency, Total

Liver insufficiency, Grade 5

Neural disorder, Total

Neural disorder, Grade 2

Noninfected perihepatic fluid collections, Total

Noninfected perihepatic fluid collections, Grade 2

Other complication, Total

Other complication, Grade 1

Other complication, Grade 2

Other complication, Grade 3

Other complication, Grade 4

Pulmonary, Total

Pulmonary, Grade 3

Renal impairment, Total

Renal impairment, Grade 2

Renal impairment, Grade 4

Wound healing, Total

Wound healing, Grade 1

Wound healing, Grade 3

Wound healing, Grade 4

Safety Population (First Surgery Subpopulation): All participants who underwent a first resective surgery and who received at least one dose of trial medication, whether prematurely withdrawn or not. Participants were analyzed according to the actual treatment they received.

Percentage of Participants With Complications Related to First Resective Surgery

Any complication, Grade 3a

Safety Population (Second Surgery Subpopulation): All participants who underwent a second resective surgery and who received at least one dose of trial medication, whether prematurely withdrawn or not. Participants were analyzed according to the actual treatment they received.

Percentage of Participants With Complications Related to Second Resective Surgery

Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (mFOLFOX-6). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 milligrams per kilogram (mg/kg) via intravenous (IV) infusion; oxaliplatin 85 milligrams per meter-squared (mg/m\^2) via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, progressive disease (PD), unacceptable toxicity, or participant refusal.

Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, irinotecan, leucovorin, and 5-FU (FOLFOXIRI). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.

Spots Global Cancer Trial Database for A Study of Avastin (Bevacizumab) in Combination With mFOLFOX-6 or FOLFOXIRI in Patients With Metastatic Colorectal Cancer.

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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