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Phase I Study of ZD6474, Cetuximab, and Irinotecan in Patients With Metastatic Colorectal Cancer

Phase 1
18 Years
Not Enrolling
Colorectal Cancer

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Trial Information

Phase I Study of ZD6474, Cetuximab, and Irinotecan in Patients With Metastatic Colorectal Cancer

- The main purpose is to find the highest dose of ZD6474 that is safe to give in
combination with cetuximab and irinotecan. We will also be collecting information on
how the body responds to the study drugs and what effects, good or bad, it has on
treatment of colon and rectal cancer.

- Initially we plan to add ZD6474 to cetuximab alone. Small groups of participants will
be enrolled in steps. The first group will be given a certain dose of ZD6474 and
cetuximab. If the participants have few or manageable side effects, the next small
group of people will receive a higher dose of ZD6474. This increase will continue
until the study doctors find the highest dose that can be given.

- Once we determine the highest dose of ZD6474 with cetuximab, we will add irinotecan at
increasing doses to determine the safety of all three drugs combined. The participant
will know whether they are receiving the two or three drug combination.

- In order to confirm the safety of combining these drugs and to understand more how they
work and interact with each other, some participants on this study will take just the
ZD6474 for 2 weeks prior to starting the cetuximab and/or irinotecan.

- Each cycle of treatment is 8 weeks long. All participants will start taking ZD6474
orally, on day one and continue taking it at home thereafter. Cetuximab and irinotecan
are given intravenously. Cetuximab is given once a week. Irinotecan will be given to
participants that enter the trial once the safe dose of ZD6474 and cetuximab is
determined. Irinotecan is given on Day 15 of cycle one, then every other week.

- Participants will be asked to visit the clinic every week for the first three weeks
they are on the study. After the first three weeks, they will be required to visit
with the doctor every other week. These visits will include physical exams, routine
blood tests, scans, and other tests or procedures to monitor health.

- In addition to routine blood tests, blood tests for research will be done on the last
10 subjects on the trial. Test results from this sample will be used to evaluate the
participants condition.

- In order to be treated on this study, a tumor tissue specimen must ba available for
research testing. The specimen will be taken from a biopsy that was done before the
participant enrolled on the study.

- Participants can continue on the study drug as long as they tolerate the drug and the
cancer does not grow.

Inclusion Criteria:

- Histologically or cytologically documented locally advanced or metastatic colorectal

- 1-2 prior therapies for metastatic colorectal cancer. Prior adjuvant therapy not
included in the number of priors unless recurrence within 12 months of last dose of
therapy and then the adjuvant therapy will be counted.

- Tumor is K-ras wildtype by method of choice at respective institution (testing codons
12 and 13)

- Measurable disease according to the RECIST criteria

- 18 years of age or older

- ECOG Performance Status of 0-2

- Completed any major surgery 4 weeks from registration and any minor surgery 2 weeks
from registration

- Adequate bone marrow function

- Adequate renal function

- Adequate hepatic function

- Normal range of serum calcium and magnesium

- Agree to use an effective form of contraception during the study and 90 days
following the last dose of medication

- Negative urine or serum pregnancy test

Exclusion Criteria:

- History of prior malignancy within the past 3 years except curatively treated basal
cell carcinoma of the skin, cervical intra-epithelial neoplasia, or treated localized
prostate cancer

- Prior therapy with gefitinib, erlotinib, cetuximab, ABX-EGF or other specific EGFR

- Known hypersensitivity to any components of each drug

- Pregnant or lactating women

- Any other medical condition, including mental illness or substance abuse, deemed by
the clinician to be likely to interfere

- Potassium < 4.0 mEg/L despite supplementation

- Evidence of severe or uncontrolled systemic disease or any concurrent illness that,
in the opinion of the investigator, makes it undesirable for the patient to
participate in the trial or which would jeopardize compliance with the protocol

- Clinically significant cardiac event such as myocardial infarction: NYHA
classification of heart disease greater than or equal to 2 that, in the opinion of
the investigator, increases the risk of ventricular arrhythmia within 3 months before
entry; or presence of cardiac disease

- History of arrythmia which is symptomatic or requires treatment or asymptomatic
sustained ventricular tachycardia

- Previous history of QTc prolongation as a result from other medication that required
discontinuation of that medication

- Congenital long QT syndrome, or 1st degree relative with unexplained sudden death
under 40 years of age

- Presence of left bundle branch block

- QTc with Bazett's correction that is unmeasurable , or greater then 480msec on
screening ECG

- Any concomitant medication that may cause QTc prolongation, induce Torsades de
Pointes or induce CYP3A4 function

- Hypertension not controlled by medical therapy

- Patients lacking physical integrity of the upper gastrointestinal tract or who have
malabsorption syndrome

- Currently active diarrhea that may affect patient's ability to absorb ZD6474 or
tolerate potential diarrhea from study drugs

- For patients entering dose levels 4-6, prior history of irinotecan toxicity requiring
a dose reduction lower than the dose of irinotecan that the patient will be receiving
on this study

- Receipt of any investigational agents within 30 days prior to commencing study

- Last dose of prior chemotherapy or radiation therapy discontinued less thn 4 weeks
before the start of study therapy

- Incompletely healed surgical incisions, at the discretion of the investigator

- Any unresolved toxicity greater than CTC grade 1 from previous anti-cancer therapy

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the tolerability and maximum tolerated dose of combining ZD6474, cetuximab and irinotecan in patients with metastatic colorectal cancer refractory to prior cytotoxic chemotherapy.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Jeffrey Meyerhardt, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

February 2007

Completion Date:

August 2012

Related Keywords:

  • Colorectal Cancer
  • ZD6474
  • cetuximab
  • irinotecan
  • Colorectal Neoplasms



Beth Israel Deaconess Medical Center Boston, Massachusetts  02215
Dana-Farber Cancer Institute Boston, Massachusetts  02115
Massachusetts General Hospital Boston, Massachusetts  02114-2617