Adjuvant Xeloda Plus Eloxatin +/- Avastin After Radical Resection of Liver Metastasis of Colorectal Cancer

This study has been terminated.
(Data from the C08 study and Avant study)
Sponsor:
Collaborators:
Sanofi
Roche Pharma AG
Information provided by (Responsible Party):
Dutch Colorectal Cancer Group
ClinicalTrials.gov Identifier:
NCT00394992
First received: November 1, 2006
Last updated: February 3, 2014
Last verified: February 2014
  Purpose

The primary aim of this study is to investigate whether the addition of the new anti-cancer drug bevacizumab (Avastin) to the combination of the chemotherapeutic agents capecitabine (Xeloda) and oxaliplatin (Eloxatin) reduces (slows down) the recurrence of metastatic disease after a radical resection of liver metastases in patients with colorectal cancer.


Condition Intervention Phase
Colorectal Cancer
Liver Metastases
Drug: oxaliplatin+capecitabine
Drug: Oxaliplatin+capecitabine+bevacizumab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase III Study Post Radical Resection of Liver Metastasis of Colorectal Cancer: Bevacizumab in Combination With XELOX as Adjuvant Chemotherapy vs XELOX Alone

Resource links provided by NLM:


Further study details as provided by Dutch Colorectal Cancer Group:

Primary Outcome Measures:
  • 3-year disease free survival, defined as the percentage of disease free patients 3 year after randomisation. [ Time Frame: study duration ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival, defined as the percentage of patients alive 5 year after randomisation. [ Time Frame: study duration ] [ Designated as safety issue: No ]

Enrollment: 79
Study Start Date: December 2006
Study Completion Date: August 2013
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1 oxaliplatin+capecitabine
postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w
Drug: oxaliplatin+capecitabine
postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w
Experimental: 2 oxaliplatin+capecitabine+bevacizumab
postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus bevacizumab 7.5 mg/kg on day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w
Drug: Oxaliplatin+capecitabine+bevacizumab
postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus bevacizumab 7.5 mg/kg on day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w

Detailed Description:

The primary therapy of colorectal cancer is surgical resection, but more than half of all colorectal cancer patients eventually die of metastatic disease. Although the introduction of new anticancer agents with efficacy in metastatic colorectal cancer, e.g.: oxaliplatin and irinotecan, and the targeted agents cetuximab and bevacizumab has changed therapeutic nihilism, chemotherapy alone has failed to cure these patients.

It is estimated that 15-20 % of colorectal cancer patients present with synchronous liver metastases and approximately 50% of the patients with colorectal tumors will develop liver metastases at some point during the course of their disease. In almost one third of the cases, the liver was shown at autopsy to be the only site of cancer spread. This is in accordance with the 20% - 45 % five-year survival obtained with surgical resection of hepatic metastases.

Previous studies have not shown a clear benefit of adjuvant chemotherapy after metastasectomy of liver metastases. However, most of these studies have been performed with 5-fluorouracil with or without other older cytostatic drugs. Since new effective agents have been developed (e.g.: capecitabine, oxaliplatin and bevacizumab), adjuvant combination treatment with these agents might be more effective. These drugs have proven activity as first line palliative treatment of recurrent metastases. This raises the question if this new effective treatment is of value as an adjuvant treatment after metastasectomy.

As mentioned before, a two-arm EORTC study: neoadjuvant and adjuvant FOLFOX vs no chemotherapy in resectable liver metastases of colorectal cancer is almost completed (Nordlinger et al). It is expected that this study will show a 10% 3 year DFS benefit in favour of th treatment arm. Definitive data of this trial will be released at the end of 2006, and will most probably lead to adjuvant treatment post metastasectomy as a standard of care. In the HEPATCIA trial we anticipate on this by using adjuvant XELOX as the control arm.

As mentioned earlier, the 3-year disease free survival in patients post metastasectomy of liver metastases is approximately 25%. There is no data available on the effectivity of the XELOX regimen as adjuvant treatment after metastasectomy of colorectal cancer metastases. The EORTC study was designed to demonstrate a 10% improvement in 3y DFS. Assuming that this study is positive, 3 year DFS would be 35% in the control arm (XELOX post liver resection).

Since bevacizumab inhibits angiogenesis, which is required for growth of metastases, this drug may be valuable in the adjuvant setting. Several studies investigate the value of this drug in combination with fluoropyrimidines as an adjuvant regimen after resection of primary colorectal cancers. However, at this moment there is no mature data available of these studies. Therefore, we assume an increase in 3-year disease free survival of 10%, to 45% in the XELOX and bevacizumab treatment arm.

This study will therefore evaluate patients with resectable liver metastasis without extra-hepatic disease, investigating whether the capecitabine, oxaliplatin and bevacizumab regimen is superior to capecitabine and oxaliplatin alone applied as adjuvant treatment, in order to extent disease free and overall survival.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed written informed consent obtained prior to any study-specific procedures.
  • Age ≥ 18 years.
  • Liver metastases radically resected (R0 resection).
  • Study medication started ≥4 and ≤ 8 weeks post liver surgery.
  • Histologically confirmed liver metastasis of colorectal cancer after surgery.
  • ECOG performance status 0 or 1.
  • Adequate hematology: ANC ≥1.5 x 109/L, platelets ≥100 x 109/L, Hb ≥5.5 mmol/L, INR ≤ 1.5, APTT < 1.5 X UNL.
  • Adequate biochemistry: total bilirubin ≤1.5 UNL, ASAT and ALAT ≤2.5 x UNL, alkaline phosphatase ≤2.5 x UNL, serum creatinine ≤1.5 UNL.
  • Urine dipstick <2+ for protein.

Exclusion Criteria:

  • Extrahepatic metastatic disease.
  • Prior adjuvant chemotherapy given <6 months prior to detection of the liver metastases.
  • Prior non colorectal malignancies.
  • Bleeding diathesis or coagulation disorders or the need for full-dose anticoagulation.
  • Major surgical procedure <4 weeks prior to start of study treatment.
  • Females with a positive pregnancy test (within 14 days before treatment start) .
  • Lactating women.
  • Fertile women (<2 years after last menstruation) and women of childbearing potential not willing to use effective means of contraception.
  • History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake.
  • Clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascular accidents (≤6 months prior to randomization), myocardial infarction (≤1 year prior to randomization), uncontrolled hypertension while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication.
  • Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
  • Known peripheral neuropathy, including oxaliplatin induced neuropathy > grade Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible.
  • Organ allografts requiring immunosuppressive therapy.
  • Serious, non-healing wound, ulcer, or bone fracture.
  • Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes.
  • Chronic, daily treatment with high-dose asprin (> 325 mg/day) or nonsteroidal anti-inflammatory medications (those known to inhibit platelet function at doses used to treat chronic inflammatory diseases). Patients can be rendered eligible by changing the treatment to COX II inhibitors.
  • Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent excluding inhaled steroids).
  • Serious intercurrent infections (uncontrolled or requiring treatment).
  • Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
  • Patients with known allergy to Chinese hamster Ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other component of the study drugs.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00394992

Locations
Netherlands
Universitair Medisch Centrum Utrecht
Utrecht, Netherlands, 3508 GA
Sponsors and Collaborators
Dutch Colorectal Cancer Group
Sanofi
Roche Pharma AG
Investigators
Principal Investigator: Richard van Hillegersberg, MD PhD Universitair Medisch Centrum Utrecht
  More Information

Additional Information:
No publications provided by Dutch Colorectal Cancer Group

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dutch Colorectal Cancer Group
ClinicalTrials.gov Identifier: NCT00394992     History of Changes
Other Study ID Numbers: HEPATICA
Study First Received: November 1, 2006
Last Updated: February 3, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Dutch Colorectal Cancer Group:
Colorectal cancer
Liver metastasis
Radical resection
Adjuvant therapy
Bevacizumab
Capecitabine
Oxaliplatin
Hepatica

Additional relevant MeSH terms:
Colorectal Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Liver Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Liver Diseases
Oxaliplatin
Capecitabine
Bevacizumab
Fluorouracil
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 17, 2014