Phase I Trial of huA33 Plus Chemotherapy in Patients With Metastatic Colorectal Cancer

Purpose of the Research Study:

huA33 is an antibody that reacts with the A33 antigen which is produced by colorectal cancers. Prior studies have shown that application of the huA33 antibody may delay the growth of tumor cells producing the respective antigen.

Oxaliplatin and 5-FU are cytotoxic agents which are considered as standard treatment in metastatic colorectal cancer. Leucovorin is a vitamin which enhances the effect of 5-FU.

The primary purpose of this study is to determine whether the combination huA33 plus oxaliplatin, 5-FU and leucovorin is safe and what side effects occur.

Description of Research Procedures:

The first step is to determine whether or not patients are eligible for participation in the study. Apart from general blood tests and x-ray studies needed, this involves testing with regard to some special requirements:

• Three tests of stool to determine if it is positive for blood.
• Women of childbearing age must have a negative pregnancy test.
• If patients ever had a treatment with similar substances like huA33 before, a blood sample needs to be tested for antibodies that may have developed against huA33.

After eligibility is established, huA33 will be administered intravenously over a period of 30 minutes once a week at a dose of 10 mg/m2. Starting on day 15 and continuing every second week, oxaliplatin, 5-FU and leucovorin are administered. Oxaliplatin and leucovorin will be given as infusions over 2 hours. Afterwards patients will receive a bolus infusion of 5-FU intravenously followed by an infusion of 5-FU over 22 hours.

The doses of oxaliplatin will be 85mg/m2, leucovorin 200mg/m2, 400mg/m2 of 5-FU as a bolus infusion and 600mg/m2 as a continuous infusion. A complete treatment cycle consists of 12 weekly treatment days.

Patients will have an interview with their doctor and a physical examination before the first day of treatment and before each therapy. Standard blood tests as well as special blood tests to measure a possible reaction of the immune system to the huA33 antibody will be done weekly and before the treatment is started. The amount of blood to be drawn will be 20-30 ml during one cycle of the study.

X-rays and/or CT scans to measure the extent of the disease will be done at the start and at week 13, which is considered to be the first day of the next cycle. Patients may continue with this treatment for up to 2 cycles.

Inclusion criteria

Patients will be eligible for enrollment if they fulfill all of the following criteria:

• Metastatic colorectal cancer.
• Histologically or cytologically proven colorectal cancer.
• Expected survival of at least 4 months.
• Not more than 2 different pretreatment regimens.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Within the 2 weeks prior to the first dose of huA33, the following vital laboratory parameters:

Lab Parameter Range

• Neutrophil count ≥ 1.5 x 10E9/L
• Platelet count ≥ 150 x 10E9/L
• Serum bilirubin ≤ 2 mg/dL
• Creatinine clearance >50 ml/ min
• Age ≥ 18 years.
• Able and willing to give valid written informed consent.

Exclusion criteria

Patients will be excluded from the study for any of the following reasons:

• Untreated active metastatic disease to the central nervous system defined as new or enlarging lesions on CT or MRI.
• Surgery or radiotherapy of brain metastases within 3 months prior to the first dose of huA33.
• Metastatic disease involving > 50% of liver volume.
• Other serious illnesses, eg, serious infections requiring antibiotics, bleeding disorders.
• Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to first dosing (6 weeks for nitrosoureas).
• Previous treatment with oxaliplatin.
• Previous treatment with huA33 monoclonal antibody or antibody fragment.

a. Positive huA33 HAHA titer - defined as greater than 3 standard deviations above the mean patient normal range by Biacore analysis.

• Concomitant treatment with systemic corticosteroids. Topical or inhalational corticosteroids are permitted.
• Known HIV, Hepatitis B or C positivity.
• Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.
• Lack of availability of the patient for clinical and laboratory follow-up assessment.
• Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dosing.
• Pregnancy or breastfeeding.
• Women of childbearing potential: Refusal or inability to use effective means of contraception.