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

A Multi-Center, Single-Arm, Pilot Study of 5-FU Based Doublet Chemotherapy Plus Bevacizumab as Neoadjuvant Therapy for Patients With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer

This open-label, single arm, multicenter study evaluated the resection rate in participants with colorectal cancer and previously untreated unresectable liver-only metastases after adding bevacizumab to 5-FU based doublet chemotherapy in the neoadjuvant setting. Participants receive standard 5-FU based chemotherapy plus Avastin bevacizumab 5 milligrams per kilogram (mg/kg) every 2 weeks for a maximum of 12 cycles combined pre- and postoperatively, unless they experienced progressive disease or unacceptable toxicity.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: 5-FU based doublet chemotherapy; Drug: bevacizumab

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100142
    • Beijing Cancer Hospital
  • Guangzhou, China, 510060
    • Sun Yet-sen University Cancer Center
  • Hangzhou, China, 310009
    • The Second Affiliated Hospital of Zhejiang University College
  • Harbin, China, 150001
    • The 2nd Affiliated Hospital of Harbin Medical University
  • Shanghai, China, 200032
    • Zhongshan Hospital Fudan University
  • Shenyang, China, 110042
    • Liaoning Cancer Hospital & Institute
  • Wuhan, China, 430022
    • Xiehe Hospital, Tongji Medical College Huazhong University of Science & Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult Chinese participants, 18-75 years of age
• Histologically confirmed adenocarcinoma in colon or rectum with primary lesion surgically removed
• Previously untreated unresectable liver-only metastases
• Liver lesions determined to be unresectable by multidisciplinary team (MDT, consisting of experienced hepatic surgeons, medical oncologist and radiologist).
• No previous treatment against liver metastases, including chemotherapy, surgery, radiotherapy, Transarterial chemoembolisation therapy (TACE) and target therapy
• Adequate hematological, renal and hepatic function
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Life expectancy greater than (>) 3 months

Exclusion Criteria:

• The relapse has occurred within 6 months of completion of the adjuvant treatment
• Expected impossible to achieve complete resection (R0 resection) and/or gain 30% residual liver volume even with responsive neoadjuvant therapy
• Participant cannot tolerate the surgery
• Other malignancies in the past 5 years, except for curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix
• Any extrahepatic metastases and/or recurrence of the primary tumor
• Any residual toxicity from previous chemotherapy (except alopecia) of National Cancer Institute Common Toxicity Criteria (NCI CTC) v.4.0 grade 2
• Hypertension crisis or encephalopathy
• Pregnant or lactating women
• Clinically significant cardiovascular disease
• Evidence of bleeding diathesis or coagulopathy
• Current or recent (within 10 days of study drug initiation) use of full dose of aspirin, clopidrogel or warfarin
• History or evidence of Central Nervous System (CNS) disease (for example, primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of stroke)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Bevacizumab

Drug: 5-FU based doublet chemotherapy; Standard 5-FU based doublet chemotherapy. Protocol did not specify any particular 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.; Drug: bevacizumab; 5 mg/kg every 2 weeks, up to 12 cycles pre- and postoperatively; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Complete Resection (R0 Resection)	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.	At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Incomplete Tumor Resection (R1 Resection)	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.	At time of surgery (up to 28 weeks), 48 hours post-surgery and 4 and 12 weeks after surgery (up to 40 weeks)
Percentage of Participants Achieving Objective Response	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.	Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Number of Participants With Disease Progression or Relapse or Death	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.	Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Progression Free Survival (PFS)	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.	Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Percent Probability (PP) of Being Alive and Progression Free at Months 3, 6, 9, 12, 15, and 18	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.	Months 3, 6, 9, 12, 15, and 18
Number of Participants With Disease Relapse or Death		Screening until disease progression or death until data cutoff on 12 May 2016 (up to approximately 3.5 years overall)
Disease Free Survival (DFS)	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.	Complete resection date up to disease relapse or death until data cutoff on 12 May 2016 (up to approximately 3.5 years)
Percent Probability Of Being Alive and Disease Free at Months 3, 6, 9, and 12		Months 3, 6, 9, and 12

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 16, 2012
• Primary Completion (ACTUAL): April 4, 2015
• Study Completion (ACTUAL): May 12, 2016

Study Registration Dates

• First Submitted: September 27, 2012
• First Submitted That Met QC Criteria: September 27, 2012
• First Posted (ESTIMATE): September 28, 2012

Study Record Updates

• Last Update Posted (ACTUAL): June 9, 2017
• Last Update Submitted That Met QC Criteria: May 11, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: ML28419

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes