This is a phase II, multicenter, target enrollment of 250 evaluable patients, open-label
study of cetuximab in patients with refractory, metastatic colorectal carcinoma. Based on
prior studies, we predict that 70 to 75% of patients will be EGFR-positive. Patients must
have documented failure after receiving either at least two chemotherapy regimens for
metastatic disease or adjuvant therapy plus one chemotherapy regimen for metastatic disease
provided that the patient progressed within 6 months of completing adjuvant therapy. Prior
chemotherapy must have included irinotecan, oxaliplatin, and a fluoropyrimidine.
Patients will receive an initial dose of cetuximab, 400 mg/m2, intravenously (i.v.) over 120
minutes, followed by weekly treatment with cetuximab, 250 mg/m2 i.v. over 60 minutes.
Patients who experience unacceptable toxicity or who have progressive disease will not
receive further cetuximab therapy.
Patients will be evaluated for a tumor response at a minimum of every 6 weeks while on
cetuximab therapy. Patients with stable disease or a partial or complete response may
continue to receive weekly cetuximab therapy, unless they are dose-delayed or discontinued
because of toxicity. Patients who have a partial or complete response must have a
confirmatory tumor assessment no less than 4 weeks after the initial evaluation
demonstrating a response.
In addition, there is a pharmacokinetic companion protocol which will determine the trough
and peak levels of cetuximab in 25 patients enrolled in the study at four to eight centers.
A pharmacologic serum sample for the determination of levels of cetuximab will be obtained
prior to the initial, fourth and sixth cetuximab infusions and 1 hour following the
completion of the initial, fourth and sixth cetuximab infusions in the first course; and
prior to and 1 hour post the completion of the first cetuximab infusion of each subsequent
course of therapy. A course of therapy is defined as six weekly infusions of cetuximab
monotherapy. ImClone will perform the pharmacokinetic analyses.
- Provided signed written informed consent.
- Histologically- or pathologically- confirmed metastatic colorectal carcinoma;
- Documented progressive disease after receiving either:
1. at least two chemotherapy regimens for metastatic disease or
2. adjuvant therapy plus one chemotherapy regimen for metastatic disease provided
that the patient progressed within 6 months of completing adjuvant therapy.
Progressive disease will be defined as progression while on treatment or within
3 months after receiving the last dose of therapy in a given regimen;
- Prior chemotherapy must have included irinotecan, oxaliplatin, and a
- Measurable disease as defined in Section 3.3.2;
- Immunohistochemical evidence of EGFr expression. Patients will be considered
eligible if their tumors demonstrate any EGFr staining, regardless of the intensity,
the cellular localization of the staining, or the percentage of cell staining.
Patients who do not have tumor tissue available for EGFr testing will undergo biopsy
of accessible tumor;
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1 at study
- Adequate recovery from recent surgery, chemotherapy, and radiation therapy. At least
4 weeks must have elapsed from major surgery, prior chemotherapy, prior treatment
with an investigational agent, or prior radiation therapy;
- Accessible for treatment and follow-up. Patients enrolled in this trial must be
treated at the participating center;
- Men and woman age 18 years or older
Source documentation of the prior treatment (e.g., hospital/clinic records, radiographic
reports) must be available to ImClone for review.
Sex and Reproductive Status Exceptions
- Women of child bearing potential (WOCBP) who are unwilling or unable to use an
acceptable method to avoid pregnancy for the entire study period and for up to 4
weeks after the study.
- Women who are pregnant or breastfeeding.
- Women with a positive pregnancy test on enrollment or prior to cetuximab
- Sexually active fertile men not using effective birth control.
Medical History and Concurrent Diseases
- Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent;
- A serious uncontrolled medical disorder that would impair the ability of the patient
to receive protocol therapy;
- A history of uncontrolled angina, arrhythmias, congestive heart failure, or left
ventricular ejection fraction (LVEF) below the institutional range of normal on a
baseline multiple gated acquisition (MUGA) scan or echocardiogram (ECHO);
- Known brain metastases;
- Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ
of the cervix. Patients with a previous malignancy but without evidence of disease
for greater than or equal to 5 years will be allowed to enter the trial;
Physical and Laboratory Test Findings
- Inadequate hematologic function defined by an absolute neutrophil count (ANC)
<1,500/mm3, a platelet count <100,000/mm3, and a hemoglobin level <9 g/dL.
- Inadequate hepatic function, defined by a total bilirubin level greater than or equal
to 1.5 times the upper limit of normal (ULN) and aspartate transaminase (AST) and
alanine transaminase (ALT) levels greater than or equal to 5 times the ULN.
- Inadequate renal function defined by a serum creatinine level >1.5 times the ULN.
Prohibited Therapies and/or Medications
- A history of cetuximab or other therapy that targeted the EGF receptor;
- A history of prior anti-cancer murine monoclonal antibody therapy;
- Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (eg, infectious disease) illness.