MDACC Study Summary SWOG C80405

Study Summary
No. SWOG C80405:.......Colorectal......Cathy Eng......Gastrointestinal Medical Oncology

Study Summary Title



Study Summary Number:	SWOG C80405

Study Title:	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 Untreated Metastatic Adenocarcinoma of the Colon or Rectum

Physician

New Patient Referral



Name:	Cathy Eng	Patients Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Dept:	Gastrointestinal Medical Oncology	Referring MD Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Phone:	713-792-2828 Contact us about clinical trials

General Information



Disease Group:	Colorectal	Supported By:	N/A

Phase of Study:	Phase III	Return Visit:	ARM A - Every 2 weeks ARM B & C - Weekly

Treatment Agents:	5-FU Bevacizumab Cetuximab Irinotecan Leucovorin Oxaliplatin	Home Care:	All treatment must be given at M. D. Anderson

Treatment Loc:	Independent Multicenter Arrangements

Estimated Length of Stay in Houston:	Hospitalization is not required.


Description/ Intervention:	The goal of this clinical research study is to compare the effectiveness of 2 drug combinations for treating patients with advanced colorectal cancer who do not have K-ras mutations in their tumor tissue: cetuximab plus combination chemotherapy, and bevacizumab plus combination chemotherapy. The safety of these 2 combinations will also be studied.

Study Objectives / Outcomes

Primary:
To determine if the addition of cetuximab to FOLFIRI (leucovorin, 5-FU, and irinotecan) or FOLFOX (leucovorin, 5-FU and oxaliplatin) chemotherapy prolongs survival compared to FOLFIRI or FOLFOX with bevacizumab in patients with untreated, advanced or metastatic colorectal cancer (CRC) who have K-ras wild type tumors.

Secondary:
To evaluate response, progression-free survival (PFS), time to treatment failure (TTF), and duration of response (DR) among patients with unresectable advanced metastatic CRC treated with bevacizumab or cetuximab in addition to chemotherapy with FOLFIRI or FOLFOX.

To evaluate toxicity and, in particular, 60-day mortality among patients with unresectable advanced metastatic CRC treated with bevacizumab or cetuximab in addition to chemotherapy with FOLFIRI or FOLFOX.

To describe patients with unresectable locally advanced or metastatic CRC cancer rendered "resectable" with chemotherapy.

To determine if there are significant differences in health-related quality of life among study patients by treatment arm (i.e. FOLFOX or FOLFIRI plus bevacizumab; FOLFOX or FOLFIRI plus cetuximab; FOLFOX or FOLFIRI plus bevacizumab and cetuximab).

To determine the degree to which patients enrolled in the clinical trial have access to prescription drug coverage to pay for the cost of supportive medication during chemotherapy and to identify the extent to which paying for costs of prescription medications is a source of hardship and worry for clinical trial participants.

To compare the effects of the different combinations of chemotherapy and biologic agents on resource utilization, cost, and utilities, and of applicable, to make estimates of marginal cost-utility.

To prospectively assess the influence of diet, obesity, physical activity, and other lifestyle habits on treatment-related toxicity, progression-free survival and overall survival in patients with stage IV CRC.

To perform correlative science studies in consenting patients.

Study Status Information



Study Activation / Registration Date:	10/03/2006

IRB Review and Approval Date:	06/09/2006

Study Type:	Phase Iii

Recruitment Status:	Closed

Projected Accrual:	2900

Enrollment Eligibility

If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:

1) 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 history of colorectal cancer treated 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.

3) 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.

4) 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.

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

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

7) Radiation must have concluded > / = 4 weeks prior to randomization.

8) 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.)

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

10) Patients on full-dose anticoagulation (e.g. warfarin) are eligible provided that both of the following criteria are met: The patients 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. The patient has no active bleeding or pathological condidition that carries a high risk of bleeding (e.g. tumor involving major vessels or known varices). Patients receiving anti-platelet agents are eligible. In addition, patients who are on daily prophylactic aspirin or anticoagulation for atrial fibrillation are eligible.

11) Non-pregnant and not nursing: 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.

12) Women of child bearing potential include any female who has experienced menarche and who has not undergone surgical sterilization or is not postmenopausal [defined as amenorrhea > / = 12 consecutive months; or women on hormone replacement therapy with documented serum follicle stimulating hormone level > 35mIU / mL]. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods to prevent pregnancy or practicing abstinence or where partner is sterile, should be considered to be of child bearing potential.

13) ECOG performance status of 0-1.

14) Age > / = 18 years old.

15) Required initial laboratory values: Granulocytes > / = 1500/ microliter; Hemoglobin > / = 9.0 grams / dL (patients may be transfused to meet this criterion); Platelet count > / = 100,000 / microliter; Creatinine < / = 1.5 x upper limits of normal; Bilirubin < / = 1.5 mg / dL; Albumin > / = 2.5 g / dL; Urinalysis < / = 1 + protein. Patients discovered to have > / = 2 + proteinura at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein / 24 hr or have a UPC < 1.0 to allow participation in the study

Exclusion Criteria:

1) Patients with a mutation in the K-ras gene are ineligible.

2) Prior systemic treatment for advanced or metastatic colorectal cancer is not allowed. Prior regional chemotherapy (e.g., hepatic arterial infusion) is also not allowed.

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

4) Prior exposure to any tyrosine kinase inhibitors or other agents (including protein products, monoclonal antibodies, antisense, etc.) that target VEGF or EGF receptors.

5) Prior treatment with bevacizumab or cetuximab.

6) 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.)

7) No previous or concurrent malignancy is allowed expect 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.

8) Patients to receive FOLFIRI: No evidence of Gilbert's Syndrome or of homozygosity for the UGT1A1*28 allele. Patients w/ Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38. Evidence of Gilbert's Syndrome includes prior finding of an isolated elevation of indirect bilirubin. UGT1A1 genotyping is not required on this study but patients known to be homozygous for the UGT1A1*28 allele are not to receive FOLFIRI. Patients w/ Gilbert's Syndrome or found to be homozygous for the UGT1A1 allele who will receive FOLFOX are eligible.

9) Sensory peripheral neuropathy of > / = grade 2 at baseline for patients who are to receive FOLFOX.

10) Known central nervous system metastases or carcinomatious meningitis.

11) Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung.

12) Pleural effusion or ascites that causes > / = grade 2 dyspnea.

13) 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 be entered at investigator discretion.

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

15) Current congestive heart failure. (New York Heart Association Class II, III or IV).

16) Significant history of bleeding events or GI perforation. Patients with history of significant bleeding episodes (e.g. hemoptysis, upper or lower GI bleeding) within 6 months of randomization are not eligible unless the source of bleeding has been resected. Patients with a history of GI perforation within 12 months of randomization are not eligible.

17) 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 significant peripheral artery disease (i.e. claudication on less than one block) or any other arterial thrombotic event are also ineligible.

18) 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.

Links

Registration Number: NCT00265850
Study Information on Clinical Trials Registry (clinicaltrials.gov)