Neo-adjuvant Therapy and the Effect on Synchronous Metastatic Growth

NCT00659022 | Unknown Phase 2 DMC

• 1 other identifier: SILENT
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

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

Conditions

Colorectal Neoplasms; Liver Neoplasms

Keywords

colorectal cancer; liver metastases; angiogenesis; metabolism

Outcome Measures

Primary Outcomes (2)

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

  12 weeks

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

  12 weeks

Secondary Outcomes (2)

• Toxicity of neo-adjuvant treatment

  12 weeks

• Complications of surgery

  4 weeks

Study Arms (4)

A

ACTIVE COMPARATOR

immediate surgery of the primary colorectal tumor, no neoadjuvant therapy

Procedure: immediate surgery (resection of primary colorectal tumor)

B

EXPERIMENTAL

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

Drug: neo-adjuvant treatment with bevacizumab

C

EXPERIMENTAL

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

Drug: neoadjuvant treatment with capecitabine and oxaliplatin

D

EXPERIMENTAL

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

Drug: neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin

Interventions

immediate surgery (resection of primary colorectal tumor) PROCEDURE

no neo-adjuvant treatment, immediate surgery

A

neo-adjuvant treatment with bevacizumab DRUG

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

Also known as: Avastin

B

neoadjuvant treatment with capecitabine and oxaliplatin DRUG

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

Also known as: Xeloda, Eloxatin

C

neo-adjuvant treatment with bevacizumab, capecitabine and oxaliplatin DRUG

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

Also known as: Avastin, Xeloda, Eloxatin

D

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (2)

The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital

Amsterdam, 1066 CX, Netherlands

RECRUITING

Radboud University Nijmegen Medical Center

Nijmegen, 6500 HB, Netherlands

RECRUITING

Related Publications (8)

• Gorelik E, Segal S, Feldman M. On the mechanism of tumor "concomitant immunity". Int J Cancer. 1981 Jun 15;27(6):847-56. doi: 10.1002/ijc.2910270618. No abstract available.

  PMID: 7287231 BACKGROUND

• O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315-28. doi: 10.1016/0092-8674(94)90200-3.

  PMID: 7525077 BACKGROUND

• O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997 Jan 24;88(2):277-85. doi: 10.1016/s0092-8674(00)81848-6.

  PMID: 9008168 BACKGROUND

• Peeters CF, Westphal JR, de Waal RM, Ruiter DJ, Wobbes T, Ruers TJ. Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients. Int J Cancer. 2004 Nov 20;112(4):554-9. doi: 10.1002/ijc.20374.

  PMID: 15382035 BACKGROUND

• Yang AD, Bauer TW, Camp ER, Somcio R, Liu W, Fan F, Ellis LM. Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy. Cancer. 2005 Apr 15;103(8):1561-70. doi: 10.1002/cncr.20942.

  PMID: 15754332 BACKGROUND

• Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004 Oct;4(10):806-13. doi: 10.1038/nrc1456.

  PMID: 15510161 BACKGROUND

• Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004 Jun 1;64(11):3731-6. doi: 10.1158/0008-5472.CAN-04-0074.

  PMID: 15172975 BACKGROUND

• Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005 Jan 7;307(5706):58-62. doi: 10.1126/science.1104819.

  PMID: 15637262 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms; Liver Neoplasms

Interventions

Bevacizumab; Neoadjuvant Therapy; Capecitabine; Oxaliplatin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Combined Modality Therapy; Therapeutics; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Coordination Complexes; Organic Chemicals

Study Officials

• Theo Ruers, PhD

  The Netherlands Cancer Institute

  PRINCIPAL INVESTIGATOR

• Kees Punt, PhD

  Radboud University Nijmegen Medical Center

  PRINCIPAL INVESTIGATOR

• Wim Oyen, PhD

  Radboud University Nijmegen Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Patricia Bottenberg, Ma ANP

CONTACT

+31-20-5122639; p.bottenberg@nki.nl

Theo Ruers, PhD

CONTACT

+31-20-5122538; t.ruers@nki.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: April 3, 2008
• First Posted: April 16, 2008
• Study Start: July 1, 2008
• Primary Completion: March 1, 2014
• Study Completion: April 1, 2014
• Last Updated: September 12, 2011

Record last verified: 2009-02

Locations

NL (2)