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Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined With FOLFOX Chemotherapy in Metastatic Colorectal Cancer (CA180048)


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Colorectal Cancer

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Trial Information

Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined With FOLFOX Chemotherapy in Metastatic Colorectal Cancer (CA180048)


Cetuximab is a drug designed to block the activity of EGFR, a protein on the surface of some
tumor cells that may cause the cells to grow. Blocking EGFR may stop or slow the growth of
tumor cells. Dasatinib is a drug that inhibits a protein called c-Src. High levels of
c-Src may make it harder for chemotherapy to work against the cancer. If dasatinib can
inhibit c-Src, the chemotherapy may be more effective against the cancer. FOLFOX is a drug
combination frequently used to treat colon or rectal cancer that has spread to other parts
of the body. FOLFOX is designed to kill rapidly dividing cells by preventing DNA (the
genetic material of cells) from duplicating.

KRAS Testing:

Recent studies have found that cetuximab, when given alone or in combination with other
chemotherapy drugs, was not effective when given to patients with colorectal cancer that had
a KRAS gene mutation.

If you take part in the Phase I part of this study, your tumor tissue from a previous
biopsy or surgery will be used to test for KRAS mutation. If you have the KRAS gene
mutation, you will not take part in this study.

If you take part in the Phase II part of this study, your tumor tissue from a previous
biopsy or surgery will be used to test for KRAS mutation. If you have the KRAS gene
mutation, you may take part in the study but you will not receive cetuximab.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
group (Phase I or Phase II) based on when you join this study.

If you are enrolled in the Phase I portion, the dose of dasatinib you will receive will
depend on when you joined the study. Three (3) to 6 participants will be entered at each
dose level. Each new group of participants will receive a higher dose, until the highest
tolerable dose is found. Once the highest tolerable dose is found, 12 participants will be
enrolled at that dose level. Your doctor will tell you what dose level you will be
receiving and how this dose compares to the doses other participants have received. The
starting dose of cetuximab and FOLFOX will be the same for all participants. The dose of
dasatinib will be increased with the next group of 3-6 participants. Every 14 days is
considered 1 study "cycle".

If you are enrolled in the Phase II portion, you will receive the dose of dasatinib found to
be best tolerated in the Phase I portion. You will also receive FOLFOX. If you do not have
the KRAS gene mutation, you will also receive cetuximab. Every 14 days is considered 1 study
"cycle".

Central Venous Catheter (CVC) Placement:

Before receiving the study drugs, you will have a CVC placed. A CVC is a sterile flexible
tube that will be placed into a large vein while you are under local anesthesia. Your
doctor will explain this procedure to you in more detail, and you will be required to sign a
separate consent form for this procedure.

Study Drug Administration:

You will take dasatinib by mouth once a day, every day during this study. Your study doctor
and research nurse will tell you how many pills you will take. Dasatinib should be taken
at the same time each day, with or without meals. If you miss a dose of dasatinib, you
should not double the next dose. It is important to take dasatinib with water, and not fruit
juices. You should not drink grapefruit juice or eat grapefruit while you are on this
study. Dasatinib should not be touched by children, pregnant women, or women who are
breastfeeding. If a caregiver must handle the drug, a protective glove should be worn.

While you are taking dasatinib, you will be given a drug diary. In this diary, you will
write down the date, the time, and the number of dasatinib tablets taken. Certain drugs and
herbal supplements may not be taken while you are receiving dasatinib. These drugs could
affect how your body breaks down dasatinib, which could have a bad effect on you. Your
doctor will give you a list of drugs and herbal supplements that you must not take while on
this study. You must tell your doctor before taking any new drugs while on this study.

On Day 1 of every cycle, you will receive oxaliplatin and LV through the CVC over about 2
hours. On Day 1, you will receive 5-FU through a portable pump for the next 46 hours. If
you are receiving cetuximab in the Phase I portion of the study, you will receive it on Days
1 and 8 through the CVC over about 2 hours. If you are receiving cetuximab in the Phase II
portion of the study, you will receive it on Day 1 through the CVC over about 2 hours.

Study Visits for Phase I:

If you are enrolled at the highest tolerable dose level, you will have 2 core liver
biopsies. The liver tissue will be studied to learn the effect of the study drugs on
stopping the protein c-Src. You will have 2 liver biopsies collected. The first liver
biopsy will be collected before you start the study drugs, and the second will be performed
in either Cycle 2 or 3. Before the liver biopsy, you will receive fluids and drugs for
relaxation and/or pain through an needle in your arm or hand. You will be awake during the
biopsy. A radiologist will find the tumor in the liver with the help of radiographic
imaging procedures such as an ultrasound or CT scan. Your skin around this area will be
cleansed, and a local anesthetic will be given. A long, hollow needle will be inserted
through the skin into the liver tumor, and a tissue sample(s) will be taken.

On Day 8, blood (about 1-2 tablespoons) will be drawn for routine tests.

You will have extra blood samples drawn (1 tablespoon each time) before receiving the study
drugs and on Day 8 of Cycles 2 and 4. This blood will be drawn at the same time as your
routine blood tests are drawn. These blood samples will be used to develop tests that may
help doctors be able to predict who will best benefit from dasatinib.

If you are enrolled in the group that receives the highest tolerable dose level, the Day 8
blood draw during cycle 2 will not be performed. Instead, blood will be collected at the
time of the liver biopsy that is to be performed between Days 8-14 of cycle 2 or 3 about 2
to 6 hours after taking the daily dose of dasatinib.

Study Visits for Phase II:

You will have extra blood samples drawn (1 tablespoon each time) before receiving the study
drugs and at the end of every 4 cycles. This blood will be drawn at the same time as your
routine blood tests are drawn. These blood samples will be used to develop tests that may
help doctors be able to predict who will best benefit from dasatinib.

Before the start of each new cycle and when you stop study treatment, you will be asked to
complete a questionnaire about any symptoms you may be experiencing. The questionnaire will
take up to 5 minutes to complete.

Once you stop receiving study drugs, the study team will contact you by telephone every 3
months to check how you are doing. Each phone call will take about 5 minutes.

Phase I and Phase II:

Before each new cycle, you will be asked questions about any side effects you may have had.
At each visit, it is important to tell the study staff about any drugs you are currently
taking. You will have a physical exam, including measurement of your vital signs and
weight. You will have a performance status evaluation. Blood (about 1-2 tablespoons) will
be drawn for routine tests.

Women who are able to become pregnant will have a blood or urine pregnancy test every month.

If you experience severe side effects, the study drugs may be delayed, stopped, or you may
receive smaller doses of the drugs.

You may remain on this study for as long as you are benefiting. You will be taken off this
study if the disease gets worse or intolerable side effects occur.

Once you are off-study, you will have an end-of-study visit. At this visit, blood (about 3
tablespoons) will be collected for routine tests. You will be asked questions about any side
effects you may have had and about any drugs you are currently taking. You will have a
physical exam, including measurement of your vital signs and weight. You will have a
performance status evaluation. If not performed recently, you will have a CT scan or MRI
scan of your chest, abdomen and pelvis to check the status of the disease. If you are having
side effects after you stop receiving the study drugs, you will be contacted by phone to
check how you are feeling, or you will have follow-up visits until the side effects have
gone away.

This is an investigational study. Dasatinib is FDA approved for the treatment of leukemia.
Its use in this study, for this disease, is considered to be investigational. Cetuximab,
5-FU, LV, and oxaliplatin are all FDA approved and commercially available for the treatment
of colorectal cancer. Up to 83 patients will take part in this study. All patients will be
enrolled at MD Anderson.


Inclusion Criteria:



1. Patient must have histologically or cytologically confirmed colorectal adenocarcinoma
with metastatic disease documented on diagnostic imaging studies

2. Phase IB: Patient must have wild type KRAS.

3. Phase IB: For the expansion cohort, only patients with liver metastases >/= 2.0 cm
amenable to percutaneous CT or U/S guided biopsy and who agree to having 2 liver
biopsies done are eligible.

4. Phase II: Patient must have known KRAS (exon 1, codon 12, 13) or sufficient available
tumor tissue from the primary tumor or metastatic site for KRAS mutation analysis
[Phase II only].

5. Patient must have previously progressed on systemic therapy for metastatic colorectal
cancer, with no limit on the number of prior regimens. For patients in the Phase II
cohort, they must have progressed on 5-FU or capecitabine and oxaliplatin [patients
with KRAS mutated tumors], and either cetuximab or panitumumab [patients with KRAS
wild type tumors].

6. (Continued from # 5) The following criteria must be met for progression. • Baseline
imaging was performed 1 month or less prior to starting regimen. • Average treatment
intensity (number of cycles received/number of cycles anticipated in absence of
delays) of greater than 70%. • Restaging study demonstrating progression 6 weeks or
less from last dose of oxaliplatin and EGFR inhibitor (if applicable). • Progression
may be by RECIST criteria or, with PI approval, clinical progression.

7. Written informed consent obtained

8. Age >/= 18 years to provide a uniform oncologic phenotype of adult-onset colorectal
cancer.

9. ECOG performance status 0-1 (Appendix E)

10. Patients must have adequate organ and marrow function defined as: ANC >/= 1,500/mm^3;
platelets >/= 100,000/ mm^3; hemoglobin >/= 9 gm/dL (may be transfused to maintain or
exceed this level); total bilirubin institution's upper limit of normal (IULN), or metastases; · Creatinine clearance > 60mL/min using Cockroft-Gault formula.

11. Women of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to the start of study medications. Childbearing potential is
defined as a woman who is not post-menopausal for 12 months or longer or is not
surgically sterile. Patients must agree to practice acceptable contraceptive methods
as outlined in the protocol.

Exclusion Criteria:

1. Recent (within 4 weeks of the first infusion of study drugs on this study), or
planned participation in another experimental therapeutic drug study. Patients who
have had any systemic chemotherapy, radiotherapy, or major surgery within 21 days
prior to the first infusion of study drugs.

2. Patients who have not recovered to other side effects due to prior treatment.

3. Patients with radiographic evidence of pleural effusions in the last 30 days prior to
enrollment.

4. Patients with known brain metastases because of their poor prognosis and because they
often develop progressive neurologic dysfunction that would confound the evaluation
of neurologic and other adverse events.

5. Female patients who are pregnant or lactating or men and women of reproductive
potential not willing to employ an effective method of birth control during treatment
and for 3 weeks after discontinuing study treatment

6. Patients with known dihydropyrimidine dehydrogenase deficiency.

7. Patients with a history of significant bleeding disorder unrelated to cancer,
including: Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease);
Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII
antibodies)

8. Patients currently taking the following drugs that are generally accepted to have a
risk of causing Torsades de Pointes:haloperidol, methadone, amiodarone, sotalol,
erythromycins, clarithromycin cisapride, chlorpromazine, bepridil, droperidol,
arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine,
sparfloxacin, lidoflazine, quinidine, procainamide, disopyramide, ibutilide,
dofetilide. Subjects who have discontinued any of these medications must have a
wash-out of at least 5 days (or 14 days for amiodarone) prior to the first dose of
dasatinib.

9. Patients with wild type KRAS tumors with a history of allergic reactions attributed
to cetuximab, oxaliplatin, 5-FU, capecitabine, or leucovorin that, previously, have
not been adequately prevented with premedications.

10. Current use of full-dose warfarin (except as required to maintain patency of
preexisting, permanent indwelling IV catheters). For subjects receiving warfarin for
catheter patency, INR should be < 1.5.

11. Current or recent (<2 week) use of aspirin (at a dose greater than 81 mg/day) or
clopidogrel.

12. Diagnosed or suspected congenital long QT syndrome

13. Any history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or Torsades de pointes).

14. Previous allergic reaction to a human monoclonal antibody.

15. Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) on both the
Fridericia [QTc = QT/RR^1/3] and Bazett's [QTc = QT/sqrtRR] correction. Bazett's
correction is calculated automatically by institutional EKG machines

16. Any of the following concurrent severe and/or uncontrolled medical conditions which
could compromise participation in the study: Uncontrolled high blood pressure
(systolic blood pressure >/= 140 and diastolic blood pressure >/= 90), history of
labile hypertension, or history of poor compliance with an antihypertensive regimen.
Unstable angina or stable angina markedly limiting ordinary physical activity.
(Angina occurs on walking one to two blocks on the level and climbing one flight of
stairs in normal conditions and at a normal pace).

17. Any of the following concurrent severe and/or uncontrolled medical conditions which
could compromise participation in the study: New York Heart Association (NYHA) >/=
grade 2 congestive heart failure; Myocardial infarction within 6 months of study
enrollment; History of stroke within 6 months of study enrollment; Unstable
symptomatic arrhythmia requiring medication (Patients with chronic atrial arrhythmia,
i.e., atrial fibrillation or paroxysmal SVT are eligible); Clinically significant
peripheral vascular disease; Uncontrolled diabetes; Serious active or uncontrolled
infection

18. History of other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition
that contraindicates the use of a study drug or that might affect the interpretation
of the results of the study or render the subject at high risk from treatment
complications

19. Inability to take oral medications.

20. Inability to comply with study and/or follow-up procedures.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Time Frame:

2 Week Cycles

Safety Issue:

Yes

Principal Investigator

Scott Kopetz, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2005-0842

NCT ID:

NCT00501410

Start Date:

April 2007

Completion Date:

April 2015

Related Keywords:

  • Colorectal Cancer
  • Colorectal Cancer
  • Dual Inhibition of EGFR
  • FOLFOX Chemotherapy
  • 5-FU
  • Cetuximab
  • Dasatinib
  • Leucovorin
  • Oxaliplatin
  • 5-Fluorouracil
  • BMS-354825
  • Eloxatin
  • Sprycel
  • C225
  • Erbitux
  • IMC-C225
  • Adrucil
  • Efudex
  • Folinic Acid
  • Colorectal Neoplasms

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030