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

• ClinicalTrials.gov Identifier: NCT01695772
• Recruitment Status: Completed
• First Posted: September 28, 2012
• Results First Posted: July 28, 2016
• Last Update Posted: June 9, 2017
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer	Drug: 5-FU based doublet chemotherapy; Drug: bevacizumab	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 16, 2012
• Actual Primary Completion Date: April 4, 2015
• Actual Study Completion Date: May 12, 2016

Arms and Interventions

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 Name: Avastin

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

China

Beijing Cancer Hospital

Beijing, China, 100142

Sun Yet-sen University Cancer Center

Guangzhou, China, 510060

The Second Affiliated Hospital of Zhejiang University College

Hangzhou, China, 310009

The 2nd Affiliated Hospital of Harbin Medical University

Harbin, China, 150001

Zhongshan Hospital Fudan University

Shanghai, China, 200032

Liaoning cancer Hospital & Institute

Shenyang, China, 110042

Xiehe Hospital, Tongji Medical College Huazhong University of Science & Technology

Wuhan, China, 430022

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01695772
• Other Study ID Numbers: ML28419
• First Posted: September 28, 2012
• Results First Posted: July 28, 2016
• Last Update Posted: June 9, 2017
• Last Verified: May 2017

• 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

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Bevacizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors