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A Phase III Trial of Irinotecan / 5-FU / Leucovorin or Oxaliplatin / 5-FU/ Leucovorin With Bevacizumab, or Cetuximab (C225), or With the Combination of Bevacizumab and Cetuximab for Patients With Untr

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Trial Conditions
  • Colorectal Cancer
What is the purpose of this trial?

PURPOSE: This randomized phase III trial is studying cetuximab and/or bevacizumab when given together with combination chemotherapy to compare how well they work in treating patients with metastatic colorectal cancer. RATIONALE: Monoclonal antibodies, such as cetuximab and bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as fluorouracil, leucovorin, oxaliplatin, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving monoclonal antibodies together with combination chemotherapy may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective with cetuximab and/or bevacizumab in treating patients with colorectal cancer.

Date & Status

Active, not recruiting

Who can Participate?

Eligibility

Ages:
18 and older

Gender:
Both

Eligibility

1. Locally Advanced or Metastatic Colorectal Cancer

1. Eligible patients must have histologically or cytologically documented
adenocarcinoma of the colon or rectum. Patients must have either locally
advanced (unresectable) or metastatic disease. Patients with resected primary
tumors who have documented metastases are eligible. Documentation of residual
disease by CT scan or surgeon's notes is required for all patients, and
histologic confirmation of metastases is strongly encouraged.

2. Patients with a history of colorectal cancer treatment by surgical resection who
develop radiological or clinical evidence of metastatic cancer do not require
separate histological or cytological confirmation of metastatic disease unless:

- Either an interval of greater than five years has elapsed between the
primary surgery and the development of metastatic disease or

- The primary cancer was stage I. Clinicians should consider biopsy of
lesions to establish the diagnosis of metastatic colorectal cancer in each
case if there is substantial clinical ambiguity regarding the nature or
source of apparent metastases.

3. At the time of randomization, the intent of this treatment must be indicated
palliative or neoadjuvant chemotherapy with the potential for resection of all
sites of metastatic disease.

2. Only patients with a wildtype K-ras gene as determined by the laboratory at the SWOG
Solid Tumor Repository or by a local CLIA-certified laboratory are eligible. Patients
with a mutation in the K-ras gene are ineligible. All patients must have available
for analysis of K-ras status at least one H and E slide and one paraffin block of the
previously resected primary colorectal tumor and/or a tumor deposit. For patients
registered and randomized based on local CLIA-certified laboratory results, SWOG
analysis will be confirmatory only.

3. Prior Treatment

1. No prior systemic treatment for advanced or metastatic colorectal cancer is
allowed. Prior regional chemotherapy (eg, hepatic arterial infusion) is also not
allowed.

- Patients may have received prior adjuvant chemotherapy that included
fluorouracil alone or in combination with fluorouracil and oxaliplatin or
irinotecan (no more than 6 months); or radiation with radiosensitizing
chemotherapy.

- The last course of adjuvant chemotherapy must have concluded > 12 months
prior to colorectal cancer recurrence.

- Patients may have received neoadjuvant chemo-radiation with capecitabine or
5-fluorouracil.

- Patients may not have received itraconazole or ketoconazole less than 4
weeks prior to randomization.

- No prior exposure to any tyrosine kinase inhibitors or other agents
(including protein products, monoclonal antibodies, antisense, etc.) that
target VEGF or EGF receptors is allowed.

- No prior treatment with bevacizumab or cetuximab.

2. Patients may not have had prior radiotherapy to greater than 25% of bone marrow.

(Standard adjuvant rectal cancer chemoradiation will not exclude patient from
protocol entry.) Radiation must have concluded ≥ 4 weeks prior to randomization.

3. Patients should have completed any major surgery ≥ 4 weeks from randomization.
Patients must have completed any minor surgery ≥ 2 weeks prior to randomization.
Patients must have fully recovered from the procedure. (Insertion of a vascular
access device is not considered major or minor surgery.)

4. No previous or concurrent malignancy is allowed except for adequately treated basal
cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which
the patient has been disease-free for five years.

5. For patients who are to receive FOLFIRI: No evidence of Gilbert's Syndrome or of
homozygosity for the UGT1A1*28 allele.

1. Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity
due to the abnormal glucuronidation of SN-38. Evidence of Gilbert's Syndrome
would include a prior finding of an isolated elevation of indirect bilirubin.

2. UGT1A1 genotyping is not required on this study. However, patients known to be
homozygous for the UGT1A1*28 allele are not to receive FOLFIRI for this study.
Patients with Gilbert's Syndrome or who are found to be homozygous for the
UGT1A1 allele who will receive FOLFOX are eligible.

6. No sensory peripheral neuropathy of ≥ grade 2 at baseline for patients who are to
receive FOLFOX.

7. No known central nervous system metastases or carcinomatous meningitis.

8. No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung.

9. No pleural effusion or ascites that causes ≥ grade 2 dyspnea.

10. No predisposing colonic or small bowel disorders in which the symptoms are
uncontrolled as indicated by baseline pattern of > 3 watery or soft stools daily in
patients without a colostomy or ileostomy. Patients with a colostomy or ileostomy may
entered at investigator discretion.

11. Patients must not have an uncontrolled seizure disorder, or active neurological
disease.

12. No current congestive heart failure (New York Heart Association Class II, III or IV)

13. Patients with history of hypertension must be well controlled ( < 160/90) on a
regimen of anti-hypertensive therapy.

14. Patients on full-dose anticoagulation (eg, warfarin) are eligible provided that both
of the following criteria are met:

1. The patient has an in-range INR (usually between 2 and 3) on a stable dose of
oral anticoagulant or be on a stable dose of low molecular weight heparin.

2. The patient has no active bleeding or pathological condition that carries a high
risk of bleeding (eg, tumor involving major vessels or known varices).

15. Patients receiving anti-platelet agents are eligible. In addition, patients who are
on daily prophylactic aspirin or anticoagulation for atrial fibrillation are
eligible.

16. No significant history of bleeding events or GI perforation:

1. Patients with a history of significant bleeding episodes (eg, hemoptysis, upper
or lower GI bleeding ) within 6 months of randomization are not eligible unless
the source of bleeding has been resected.

2. Patients with a history of GI perforation within 12 months of randomization are
not eligible.

17. No arterial thrombotic events within 6 months before randomization, including
transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina or
angina requiring surgical or medical intervention in the past 6 months, or myocardial
infarction (MI). Patients with clinically significantly peripheral artery disease
(eg, claudication on less than one block) or any other arterial thrombotic event are
also ineligible.

18. No serious or non-healing wound, ulcer or bone fracture

19. Patients with known hypersensitivity to Chinese hamster ovary cell products or to
recombinant human or murine antibodies are not eligible.

20. Non-pregnant and not nursing:

1. Women of child bearing potential must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours
prior to randomization.

2. DNA alkylating agents are known to be teratogenic, and the effects of
irinotecan, oxaliplatin, 5-FU, bevacizumab, and cetuximab on a developing fetus
at the recommended therapeutic doses are unknown.

3. Women of child-bearing potential include any female who has experienced menarche
and who has not undergone surgical sterilization (hysterectomy, bilateral tubal
ligation or bilateral oophorectomy) or is not postmenopausal.

4. Postmenopausal is defined as amenorrhea ≥ 12 consecutive months or women on
hormone replacement therapy (HRT) with documented serum follicle stimulating
hormone (FSH) level > 35 mIU/mL.

5. Women of child-bearing potential also include women who are using oral,
implanted or injectable contraceptive hormones or mechanical products such as an
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to
prevent pregnancy or practicing abstinence or where partner is sterile (eg,
vasectomy), should be considered to be of child bearing potential.

21. ECOG Performance Status of 0-1

22. Age ≥ 18 years

23. Required Initial Laboratory Values:

1. Granulocytes ≥ 1500 µL

2. Hemoglobin ≥ 9.0 grams/dL (patient may be transfused to meet this
criterion)

3. Platelet count ≥ 100,000/µL

4. Creatinine ≤ 1.5 x Upper limits of normal

5. Bilirubin ≤ 1.5 mg/dL

6. Albumin ≥ 2.5 g/dL

7. Urinalysis ≤ 1 + protein*

- *Patients discovered to have ≥ 2+ proteinuria at baseline must undergo a
24-hour urine collection that must demonstrate < 1 g of protein/24 hour or
have a UPC < 1.0 to allow participation in the study.

Gender: Both
Steward Physician(s)
  • Alan Venook, MD
  • Charles D. Blanke, MD, FACP
Facilities
  • St. Elizabeth's Medical Center - Active, not recruiting
  • Norwood Hospital - Active, not recruiting
Trial Interventions
Biological
  • bevacizumab
  • cetuximab
Drug
  • FOLFOX or
  • FOLFIRI
Physician Researcher

Investigator Name:

  • Alan Venook, MD
  • Charles D. Blanke, MD, FACP

Other Information

Sponsor: Alliance for Clinical Trials in Oncology
Phase: Phase 3
Trial ID: NCT00265850
Volunteers:  Not Accepting Healthy Volunteers

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