Trial Outcomes & Findings for A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer (NCT NCT01695772)

Results Overview

R0 resection was defined as complete resection confirmed by pathology after pre-operative chemotherapy plus bevacizumab. Participants with R0 resections based on assessments performed at time of surgery, 48 hours post-surgery and 4 and 12 weeks after surgery were reported.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

50 participants

Primary outcome timeframe

At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks)

Results posted on

2017-06-09

Participant Flow

Protocol did not specify any particular 5-Flurouracil (5-FU) based doublet chemotherapy regimen. The choice of 5-FU based doublet chemotherapy was as per standard of practice and the dosage of 5-FU based doublet chemotherapy was as per product labels.

Participant milestones

Participant milestones
Measure	Bevacizumab Participants received standard 5-Flurouracil (5-FU) based chemotherapy plus bevacizumab 5 milligrams per kilograms (mg/kg) intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Overall Study STARTED	50
Overall Study COMPLETED	12
Overall Study NOT COMPLETED	38

Reasons for withdrawal

Reasons for withdrawal
Measure	Bevacizumab Participants received standard 5-Flurouracil (5-FU) based chemotherapy plus bevacizumab 5 milligrams per kilograms (mg/kg) intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Overall Study Withdrawal by Subject	18
Overall Study Progressive Disease	8
Overall Study Investigator Decision	5
Overall Study Lost to Follow-up	4
Overall Study Protocol Violation	2
Overall Study Unspecified Reason	1

Baseline Characteristics

A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab n=50 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Age, Continuous	56.1 years STANDARD_DEVIATION 9.71 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants
Sex: Female, Male Male	39 Participants n=5 Participants

PRIMARY outcome

Timeframe: At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks)

Population: ITT population

R0 resection was defined as complete resection confirmed by pathology after pre-operative chemotherapy plus bevacizumab. Participants with R0 resections based on assessments performed at time of surgery, 48 hours post-surgery and 4 and 12 weeks after surgery were reported.

Outcome measures

Outcome measures
Measure	Bevacizumab n=50 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Percentage of Participants Achieving Complete Resection (R0 Resection)	30.0 percentage of participants Interval 17.9 to 44.6

SECONDARY outcome

Timeframe: At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks)

Population: ITT population

R1 resection was defined as achievement of incomplete tumor resection with microscopic involvement of a margin after pre-operative chemotherapy plus bevacizumab, as confirmed by pathology. Participants with R1 resections based on assessments performed at time of surgery, 48 hours post-surgery and 4 and 12 weeks after surgery were reported.

Outcome measures

Outcome measures
Measure	Bevacizumab n=50 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Percentage of Participants Achieving Incomplete Tumor Resection (R1 Resection)	0.0 percentage of participants Interval 0.0 to 7.1

SECONDARY outcome

Timeframe: Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)

Population: ITT population

Objective response rate was defined as the percentage of participants who achieved either Partial Response (PR) or Complete Response (CR) per Response Evaluation Criteria In Solid Tumors (RECIST) version (v) 1.1. This is defined as the best response recorded from the start of trial treatment until disease progression (or death). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than \[\<\] 10 mm). No new lesions. PR was defined as greater than or equal to \[≥\] 30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

Outcome measures

Outcome measures
Measure	Bevacizumab n=50 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Percentage of Participants Achieving Objective Response	30.0 percentage of participants Interval 17.9 to 44.6

SECONDARY outcome

Timeframe: Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)

Population: ITT population

According to RECIST v1.1 Progressive Disease is defined as a 20 % or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions.

Outcome measures

Outcome measures
Measure	Bevacizumab n=50 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Number of Participants With Disease Progression or Relapse or Death	28 participants

SECONDARY outcome

Timeframe: Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)

Population: ITT population

Progressive Disease is defined as a 20% or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions. PFS was defined as the time from initiation of study treatment to disease progression, as determined by the investigator using RECIST v1.1 criterion, or relapse after resection of liver metastases or death from any cause. Kaplan-Meier curves were used to display PFS.

Outcome measures

Outcome measures
Measure	Bevacizumab n=50 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Progression Free Survival (PFS)	12.06 months Interval 6.7 to 13.31

SECONDARY outcome

Timeframe: Months 3, 6, 9, 12, 15, and 18

Population: ITT population; Number of participants analyzed equals (=) number of participants who had surgery.

Progressive Disease is defined as a 20% or greater increase in the sum of the longest diameter of measured lesions (target lesions) taking as reference the smallest lesion diameter recorded since the treatment started or appearance of one or more new non-target lesions. PFS was defined as the time from initiation of study treatment to disease progression, as determined by the investigator using RECIST v1.1 criterion, or relapse after resection of liver metastases or death from any cause. The probability was estimated by Kaplan Meier curve analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab n=17 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 3 Months	97.7 PP of being alive and progression free Interval 84.9 to 99.7
Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 6 Months	76.4 PP of being alive and progression free Interval 59.4 to 87.0
Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 9 Months	59.5 PP of being alive and progression free Interval 40.8 to 74.0
Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 12 Months	51.5 PP of being alive and progression free Interval 32.6 to 67.5
Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 15 Months	30.0 PP of being alive and progression free Interval 14.0 to 47.9
Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18 18 Months	21.4 PP of being alive and progression free Interval 8.1 to 38.9

SECONDARY outcome

Timeframe: Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)

Population: ITT population

Outcome measures

Outcome measures
Measure	Bevacizumab n=50 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Number of Participants With Disease Relapse or Death	20 participants

SECONDARY outcome

Timeframe: Complete resection date up to disease relapse or death until data cutoff on 12 May 2016 (up to approximately 3.5 years)

Population: ITT population; Here, number of participants analyzed = participants who underwent study specified surgery. Participants who underwent surgery but did not achieve complete resection were censored.

Disease Free Survival (DFS) was defined as the time from complete resection of liver metastases to disease relapse or death, for participants who achieve complete resection after pre-operative treatment with standard 5-FU based doublet regimen plus bevacizumab.

Outcome measures

Outcome measures
Measure	Bevacizumab n=17 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Disease Free Survival (DFS)	8.48 months Interval 1.84 to 10.09

SECONDARY outcome

Timeframe: Months 3, 6, 9, and 12

Population: ITT population

Outcome measures

Outcome measures
Measure	Bevacizumab n=50 Participants Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 3 Months	80.0 PP of being alive and disease free Interval 40.9 to 94.6
Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 6 Months	70.0 PP of being alive and disease free Interval 32.9 to 89.2
Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 9 Months	40.0 PP of being alive and disease free Interval 12.3 to 67.0
Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12 12 Months	20.0 PP of being alive and disease free Interval 3.1 to 47.5

Adverse Events

Bevacizumab

Serious events: 4 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Bevacizumab n=50 participants at risk Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Infections and infestations Abdominal infection	2.0% 1/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Infections and infestations Scrotal infection	2.0% 1/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Investigations Alanine aminotransferase increased	2.0% 1/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Investigations Aspartate aminotransferase increased	2.0% 1/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Vascular disorders Deep vein thrombosis	2.0% 1/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)

Other adverse events

Other adverse events
Measure	Bevacizumab n=50 participants at risk Participants received standard 5-FU based chemotherapy plus bevacizumab 5 mg/kg intravenous infusion every two week cycle for a maximum of 12 cycles unless they experienced progressive disease, unacceptable toxicities or participant refusal.
Investigations Alanine aminotransferase increased	14.0% 7/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Investigations Aspartate aminotransferase increased	14.0% 7/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Investigations Neutrophil count decreased	14.0% 7/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Investigations White blood cell count decreased	10.0% 5/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Gastrointestinal disorders Nausea	14.0% 7/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Gastrointestinal disorders Vomiting	8.0% 4/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
General disorders Injection site reaction	14.0% 7/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Vascular disorders Hypertension	22.0% 11/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Blood and lymphatic system disorders Bone marrow failure	12.0% 6/50 • Adverse events were recorded from the date of Screening until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 1-800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER