UAB 0144

A Phase II Study of Oral Xeloda® in Combination with Intravenous Irinotecan for Patients with Locally Advanced and/or Metastatic Colorectal Cancer (Sponsor Protocol ML16323)

SPONSOR: Roche Laboratories, Inc.

PRINCIPAL INVESTIGATOR: Wasif Saif, M.D.

OBJECTIVES

1. The primary objective is to evaluate the overall objective response rate (complete and partial responses) of Capecitabine and irinotecan as first-line treatment of patients with locally advanced and/or metastatic colorectal cancer.
2. To evaluate time to progression, time to overall response, duration of overall response, duration of overall complete response, and time to treatment failure.
3. To determine one-year survival and overall survival.
4. To evaluate toxicity and the safety profile of the combination of Capecitabine and irinotecan in this patient population.
5. To evaluate the feasibility of predicting responses to Capectabine and irinotecan by the molecular profile of patient's tumor tissues.

PATIENT SELECTION

Inclusion Criteria

1. Provide written informed consent prior to study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
2. Be at least 18 years of age.
3. Patients who are ambulatory and have a Karnofsky Performance Status of > 80%
4. Histologically confirmed colorectal adenocarcinoma with locally advanced (including locally recurrent) and/or metastatic disease.
5. At least one measurable lesion according to RECIST criteria which has not been irradiated (i.e., newly arising lesions in previously irradiated areas are acceptable). Bone metastases, ascites and pleural effusions are not considered as measurable.
6. Minimum indicator lesion size as follows:
   • > 10mm measured by spiral CT
   • > 20mm measured by conventional techniques
7. Women of childbearing potential must have a negative serum pregnancy test within 1 week prior to study start. The sensitivity must be equal to at least 50mlU/ml.
8. Paraffin blocks/slides of tissue from the primary tumor and at least one metastatic site or site of local advancement must be available for shipment to Covance Laboratories prior to study enrollment. Only those patients who consent to the use of their tumor tissue and blood sample for biomarker analysis will be eligible for enrollment.

Exclusion Criteria

1. Pregnant or lactating women.
2. Women of childbearing potential with either a positive or no pregnancy test at baseline.
3. Women of childbearing potential unless using a reliable and appropriate contraceptive method. (Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential).
4. Sexually active males unwilling to practice contraception during the study.
5. Prior active or passive immunotherapy or cytotoxic chemotherapy except given as neoadjuvant or adjuvant treatment and completed at least 12 months prior to the initiation of study treatment.
6. Prior unanticipated severe reaction to fluoropyrimidine therapy (DPD deficiency) or known hypersensitivity to 5-fluorouracil.
7. Prior chemotherapy regimens for metastatic colorectal cancer.
8. Known Gilbert's disease.
9. Radiotherapy within 4 weeks of treatment start or prior radiotherapy to the indicator lesion(s) being measured in the study (newly arising marker lesions in previously irradiated areas are accepted) or patients with planned radiotherapy during study drug treatment or follow-up.
10. Evidence of CNS metastases. Patients with a history of uncontrolled seizures or central nervous system disorders.
11. History of a psychological illness or condition which would interfere with the patient's ability to understand the requirements of the study.
12. History of another malignancy within the last five years except cured basal cell carcinoma of skin and carcinoma in situ of uterine cervix.
13. Clinically significant cardiac disease (e.g., congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months.
14. Following laboratory values:
    • Granulocytes or neutrophils < 1.5 x 109/L
    • Platelet count < 100 x 109/L
    • Serum creatinine > 1.5 x upper limit of normal
    • Any patient with an estimated creatinine clearance < 50ml/min (calculated with Cockcroft-Gault equation).
    • Serum bilirubin > 1.25 x upper limit of normal
    • ALAT, ASAT > 2.5 x upper limit of normal without liver metastases or > 5 x upper limit of normal in case of liver metastases.
    • Alkaline phosphatase > 2.5 x upper limit of normal or > 5 x upper limit of normal in case of liver metastases or > 10 x upper limit of normal in case of bone metastases.
15. Major surgery within 4 weeks prior to study enrollment start, or without complete recovery.
16. Serious concurrent infections.
17. Patients who have had an organ allograft.
18. Lack of physical integrity of the upper gastrointestinal tract, inability to swallow tablets or those who have malabsorption syndrome.
19. Participation in any investigational drug study within 4 weeks preceding treatment start.
20. Hypersensitivity to 5-fluorouracil, any of the components of Capecitabine, or irinotecan.

ADDITIONAL INFORMATION

For further information, contact Sandra Sellers, RN, BSN, OCN at (205) 975-7162 or page through the UAB Paging Operator at (205) 934-3411, Pager #5819.