Cetuximab and/or Bevacizumab Combined With Combination Chemotherapy in Treating Patients With Metastatic Colorectal Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: bevacizumab; cetuximab; FOLFOX or; FOLFIRI
Intervention description: Given IV; Given IV; Patients receive oxaliplatin 85 mg/m^2 IV infused over two hours followed by leucovorin 400 mg/m^2 IV over 2 hours followed by 5-FU 400 mg/m^2 IV bolus, then 2400 mg/m^2 continuous IV infusion over 46-48 hours; Patients receive irinotecan 180 mg/m^2 IV infused over 90 minutes followed by leucovorin 400 mg/m^2 IV over 2 hours followed by 5-FU 400 mg/m^2 IV bolus following leucovorin then 2400 mg/m^2 continuous IV infusion over 46-48 hours.
Intervention MeSH terms: Leucovorin; Folic Acid; Bevacizumab; Cetuximab; Fluorouracil; Oxaliplatin; Irinotecan; Levoleucovorin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 2334.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: recurrent colon cancer; stage III colon cancer; stage III rectal cancer; stage IV colon cancer; recurrent rectal cancer; stage IV rectal cancer; adenocarcinoma of the colon; adenocarcinoma of the rectum

Summary:

      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.
    

Eligibility criteria:

        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.