ZD6474, Cetuximab, and Irinotecan in Patients With Metastatic Colorectal Cancer

October 3, 2012 updated by: Jeffrey A. Meyerhardt, MD, Dana-Farber Cancer Institute

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

This research study will test the safety of the investigational drug, ZD6474, in combination with 2 other drugs that are standard in the treatment of colon and rectal cancer (cetuximab and irinotecan). ZD6474 blocks the action of two substances in the body: vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). VEGFR stimulates the formation of new blood vessels. When cancer cells produce VEGFR, new blood vessels are made that provide blood to the cancer cells. The blood carries nutrients and oxygen, allowing the cancer cells to live and grow. EGFR controls how quickly cells grow and multiply. Both of these substances are found on normal cells, but they are found in much higher levels on cancer cells.

Study Overview

Status

Completed

Conditions

Colorectal Cancer

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

Phase

Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

Inclusion Criteria:

Histologically or cytologically documented locally advanced or metastatic colorectal cancer
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 inhibitor
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 treatment
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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Interventional Model: Single Group Assignment
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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. Time Frame: Years	Years

Secondary Outcome Measures

Outcome Measure	Time Frame
Determine response rate, progression-free survival and overall survival of adding ZD6474 to cetuximab and irinotecan in this patient population. Time Frame: Years	Years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Dana-Farber Cancer Institute

Collaborators

Massachusetts General Hospital

Beth Israel Deaconess Medical Center

AstraZeneca

Investigators

Principal Investigator: Jeffrey Meyerhardt, MD, Dana-Farber Cancer Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Meyerhardt JA, Ancukiewicz M, Abrams TA, Schrag D, Enzinger PC, Chan JA, Kulke MH, Wolpin BM, Goldstein M, Blaszkowsky L, Zhu AX, Elliott M, Regan E, Jain RK, Duda DG. Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with previously treated metastastic colorectal cancer. PLoS One. 2012;7(6):e38231. doi: 10.1371/journal.pone.0038231. Epub 2012 Jun 12.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2007

Primary Completion (Actual)

February 1, 2012

Study Completion (Actual)

August 1, 2012

Study Registration Dates

First Submitted

February 15, 2007

First Submitted That Met QC Criteria