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Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth

Primary Purpose

Colorectal Neoplasms, Liver Neoplasms

Status

Unknown status

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

immediate surgery (resection of primary colorectal tumor)

neo-adjuvant treatment with bevacizumab

neoadjuvant treatment with capecitabine and oxaliplatin

neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin

About this trial

This is an interventional treatment trial for Colorectal Neoplasms focused on measuring colorectal cancer, liver metastases, angiogenesis, metabolism

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with histological proven primary colorectal cancer and synchronous unresectable liver metastases with or without additional extrahepatic disease (primary tumor in situ). Unresectable liver metastases defined as too extensive hepatic involvement or extrahepatic disease.
Measurable liver metastases on CT scan (RECIST), positive signal of liver metastases on FDG-PET scan
Age: 18-80 years
WHO performance scale 0-1
ASA category I or II
Negative pregnancy test in women with childbearing potential
Life expectancy > 12 weeks
Laboratory values obtained ≤ 3 weeks prior to study entry, disease evaluation performed ≤ 3 weeks prior to study entry. Adequate bone marrow function (Hb > 6.5 mmol/L, absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L), renal function (serum creatinine < 1.5 x ULN or creatinine clearance ≥ 50 mL/min (calculated according to Cockroft and Gault), liver function (ASAT and ALAT ≤ 3 x upper normal limit, serum bilirubin ≤ 2 x upper normal limit)
Written informed consent

Exclusion Criteria:

Signs of bowel obstruction or bleeding from primary tumor
Prior chemotherapy treatment for advanced disease, prior treatment with anti-angiogenic drugs
Resectable liver metastases
Diabetes mellitus
Continuous use of immunosuppressive agents
Pregnancy or lactation
Contra-indications for systemic therapy with bevacizumab (Avastin)/ chemotherapy (Xelox)
Concurrent severe or uncontrolled disease (i.e. uncontrolled hypertension, congestive heart failure, myocardial infarction < 12 months, chronic active infection)
Sensory neuropathy > grade 1
Serious non-healing wound or ulcer
Patients (M/F) with reproductive potential not implementing adequate contraceptive measures
Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to start of bevacizumab
Bleeding disorders or coagulopathy or need for full-dose anticoagulation
Signs or symptoms of brain metastases
Cerebrovascular accident or transient ischemic attack within the past 12 months
Impairment of gastrointestinal function or -disease that may significantly impair the absorption of oral drugs (i.e. uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow tablets)
Presence of proteinuria at baseline as defined by: patients with > 1 g of protein/24 hr by a 24-hour urine collection.
Any concomitant disorder preventing the safe administration of study drugs or surgical procedure.

Sites / Locations

The Netherlands Cancer Institute/ Antoni van Leeuwenhoek HospitalRecruiting
Radboud University Nijmegen Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Arm Label

Arm Description

immediate surgery of the primary colorectal tumor, no neoadjuvant therapy

neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary

neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary

neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary

Outcomes

Primary Outcome Measures

Difference in response of liver metastases between control group and experimental groups determined by histopathological scoring of vascular density,apoptotic and mitotic index

Difference in response of liver metastases between control group and experimental groups determined by FDG-PET

Secondary Outcome Measures

Toxicity of neo-adjuvant treatment

Complications of surgery

Full Information

NCT ID

NCT00659022

First Posted

April 3, 2008

Last Updated

September 9, 2011

Sponsor

Radboud University Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT00659022

Brief Title

Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth

Official Title

Accelerated Growth of Synchronous Colorectal Liver Metastases: Effects of Neo-adjuvant Therapy

Study Type

Interventional

2. Study Status

Record Verification Date

February 2009

Overall Recruitment Status

Unknown status

Study Start Date

July 2008 (undefined)

Primary Completion Date

March 2014 (Anticipated)

Study Completion Date

April 2014 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor

Radboud University Medical Center

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Study Hypothesis • As well as in animal models as in patients with colorectal cancer resection of the primary tumor resulted in increase in vascular density, metabolism and secondary tumor growth of the distant metastases. These data strongly suggest an inhibitory effect of the primary tumor on the outgrowth of its metastases. In this study we investigate whether pre-operative treatment with the anti-angiogenic agent bevacizumab and/or chemotherapy before resection of the primary colorectal tumor shifts the balance between angiogenic and anti-angiogenic factors in favor of the anti-angiogenic factors and results in reduced growth of the liver metastases. Eligibility Histological proven colorectal cancer without signs of bowel obstruction or bleeding Synchronous liver metastases WHO performance status 0-1 Treatment Arm A: immediate surgery of the primary colorectal tumor, no neoadjuvant therapy Arm B: neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary Arm C: neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary Arm D: neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary Primary endpoint Difference in response of liver metastases to resection of the primary tumor between the experimental groups and the control group, as determined by histopathological scoring of vascular density, apoptotic and mitotic index and by measurement of the metabolic activity of liver metastases by FDG-PET and SUV measurements. Secondary endpoints Toxicity of neo-adjuvant treatment Complications of surgery

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Neoplasms, Liver Neoplasms

Keywords

colorectal cancer, liver metastases, angiogenesis, metabolism

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Active Comparator

Arm Description

immediate surgery of the primary colorectal tumor, no neoadjuvant therapy

Arm Title

Arm Type

Experimental

Arm Description

neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary

Arm Title

Arm Type

Experimental

Arm Description

neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary

Arm Title

Arm Type

Experimental

Arm Description

neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary

Intervention Type

Procedure

Intervention Name(s)

immediate surgery (resection of primary colorectal tumor)

Intervention Description

no neo-adjuvant treatment, immediate surgery

Intervention Type

Drug

Intervention Name(s)

neo-adjuvant treatment with bevacizumab

Other Intervention Name(s)

Avastin

Intervention Description

neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary

Intervention Type

Drug

Intervention Name(s)

neoadjuvant treatment with capecitabine and oxaliplatin

Other Intervention Name(s)

Xeloda, Eloxatin

Intervention Description

neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary

Intervention Type

Drug

Intervention Name(s)

neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin

Other Intervention Name(s)

Avastin, Xeloda, Eloxatin

Intervention Description

neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary

Primary Outcome Measure Information:

Title

Difference in response of liver metastases between control group and experimental groups determined by histopathological scoring of vascular density,apoptotic and mitotic index

Time Frame

12 weeks

Title

Difference in response of liver metastases between control group and experimental groups determined by FDG-PET

Time Frame

12 weeks

Secondary Outcome Measure Information:

Title

Toxicity of neo-adjuvant treatment

Time Frame

12 weeks

Title

Complications of surgery

Time Frame

4 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with histological proven primary colorectal cancer and synchronous unresectable liver metastases with or without additional extrahepatic disease (primary tumor in situ). Unresectable liver metastases defined as too extensive hepatic involvement or extrahepatic disease. Measurable liver metastases on CT scan (RECIST), positive signal of liver metastases on FDG-PET scan Age: 18-80 years WHO performance scale 0-1 ASA category I or II Negative pregnancy test in women with childbearing potential Life expectancy > 12 weeks Laboratory values obtained ≤ 3 weeks prior to study entry, disease evaluation performed ≤ 3 weeks prior to study entry. Adequate bone marrow function (Hb > 6.5 mmol/L, absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L), renal function (serum creatinine < 1.5 x ULN or creatinine clearance ≥ 50 mL/min (calculated according to Cockroft and Gault), liver function (ASAT and ALAT ≤ 3 x upper normal limit, serum bilirubin ≤ 2 x upper normal limit) Written informed consent Exclusion Criteria: Signs of bowel obstruction or bleeding from primary tumor Prior chemotherapy treatment for advanced disease, prior treatment with anti-angiogenic drugs Resectable liver metastases Diabetes mellitus Continuous use of immunosuppressive agents Pregnancy or lactation Contra-indications for systemic therapy with bevacizumab (Avastin)/ chemotherapy (Xelox) Concurrent severe or uncontrolled disease (i.e. uncontrolled hypertension, congestive heart failure, myocardial infarction < 12 months, chronic active infection) Sensory neuropathy > grade 1 Serious non-healing wound or ulcer Patients (M/F) with reproductive potential not implementing adequate contraceptive measures Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to start of bevacizumab Bleeding disorders or coagulopathy or need for full-dose anticoagulation Signs or symptoms of brain metastases Cerebrovascular accident or transient ischemic attack within the past 12 months Impairment of gastrointestinal function or -disease that may significantly impair the absorption of oral drugs (i.e. uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow tablets) Presence of proteinuria at baseline as defined by: patients with > 1 g of protein/24 hr by a 24-hour urine collection. Any concomitant disorder preventing the safe administration of study drugs or surgical procedure.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Patricia Bottenberg, Ma ANP

Phone

+31-20-5122639

p.bottenberg@nki.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Theo Ruers, PhD

Phone

+31-20-5122538

t.ruers@nki.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Theo Ruers, PhD

Organizational Affiliation

The Netherlands Cancer Institute

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Kees Punt, PhD

Organizational Affiliation

Radboud University Nijmegen Medical Center

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Wim Oyen, PhD

Organizational Affiliation

Radboud University Nijmegen Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital

City

Amsterdam

ZIP/Postal Code

1066 CX

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Theo Ruers, PhD

Phone

+31-20-5122538

t.ruers@nki.nl

Facility Name

Radboud University Nijmegen Medical Center

City

Nijmegen

ZIP/Postal Code

6500 HB

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kees Punt, PhD

Phone

+31-24-3610353

C.Punt@onco.umcn.nl

12. IPD Sharing Statement

Citations:

PubMed Identifier

7287231

Citation

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Results Reference

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PubMed Identifier

7525077

Citation

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Results Reference

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PubMed Identifier

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Citation

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Results Reference

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PubMed Identifier

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Citation

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Citation

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Citation

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PubMed Identifier

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Citation

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Results Reference

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Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth

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