A Phase II Study of Axitinib as Maintenance Treatment for Patients With Metastatic Colorectal Carcinoma
1. Patient must have histological or cytological confirmed colorectal adenocarcinoma
with metastatic disease documented on diagnostic imaging studies, not susceptible of
radical surgery of metastases, and a low burden of disease.
2. Patients without progressive disease after six months of the standard first line
chemotherapy regimen for CRC (5FU or capecitabine ± oxaliplatin or irinotecan ±
bevacizumab or cetuximab).
3. Patient must have at least one measurable lesion as defined by modified RECIST
4. Male or female, age ≥18 years.
5. ECOG performance status of 0 or 1 and life expectancy of ≥12 weeks.
6. Adequate organ function as defined by the following criteria:
- absolute neutrophil count (ANC) ≥1500 cells/mm3;
- platelets ≥100,000 cells/mm3.
- Hemoglobin ≥9.0 g/dL.
- AST and ALT ≤2.5 x upper limit of normal (ULN), unless there are liver
metastases in which case AST and ALT ≤5.0 x ULN;
- Total bilirubin ≤1.5 x ULN;
- Alkaline phosphatase <300U/l
- Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥50 mL/min;
- Urinary protein <2+ by urine dipstick. If dipstick is ≥2+ then a 24-hour urine
collection can be done and the patient may enter only if urinary protein is <2 g
per 24 hours.
7. At least 4 weeks since the end of prior systemic treatment, radiotherapy, or surgical
procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 4.0
grade ≤1 or back to baseline except for alopecia or neurotoxicity
8. No evidence of pre existing uncontrolled hypertension as documented by 2 baseline
blood pressure readings taken at least 1 hour apart. The baseline systolic blood
pressure readings must be ≤140 mm Hg, and the baseline diastolic blood pressure
readings must be ≤90 mm Hg. Patients whose hypertension is controlled by
antihypertensive therapies are eligible.
9. Women of childbearing potential must have a negative serum or urine pregnancy test
within 3 days prior to treatment.
10. Signed and dated informed consent document indicating that the patient (or legally
acceptable representative) has been informed of all pertinent aspects of the trial
prior to enrollment.
11. Willingness and ability to comply with scheduled visits, treatment plans (including
willingness to take either AG-013736 or placebo according to randomization),
laboratory tests, and other study procedures.
1. Gastrointestinal abnormalities including:
- inability to take oral medication;
- requirement for intravenous alimentation;
- prior surgical procedures affecting absorption including total gastric
- treatment for active peptic ulcer disease in the past 6 months;
- active gastrointestinal bleeding, unrelated to cancer, as evidenced by
hematemesis, hematochezia or melena in the past 3 months without evidence of
resolution documented by endoscopy or colonoscopy;
- malabsorption syndromes.
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to start, unless affected area has been removed
2. Current use or anticipated need for treatment with drugs that are known potent CYP3A4
inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir,
nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine).
3. Current use or anticipated need for treatment with drugs that are known CYP3A4 or
CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole,
phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin,
and St. John's wort).
4. History of haemorrhage within the past 6 months, including gross hemoptysis or
5. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
anticoagulants for maintenance of patency of central venous access devise or
prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular
weight heparin is allowed.
6. Active seizure disorder or evidence of brain metastases, spinal cord compression, or
7. A serious uncontrolled medical disorder or active infection that would impair their
ability to receive study treatment.
8. Any of the following within the 12 months prior to study drug administration:
myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft,
symptomatic congestive heart failure, cerebrovascular accident or transient ischemic
attack and 6 months for deep vein thrombosis or pulmonary embolism.
9. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial fibrillation of any grade,
or QTc interval >450 msec for males or >470 msec for females.
10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
11. History of a malignancy (other than colorectal cancer) except those treated with
curative intent for skin cancer (other than melanoma), in situ breast or in situ
cervical cancer, or those treated with curative intent for any other cancer with no
evidence of disease for 2 years.
12. Dementia or significantly altered mental status that would prohibit the understanding
or rendering of informed consent and compliance with the requirements of this
13. Female patients who are pregnant or lactating, or men and women of reproductive
potential not willing or not able to employ an effective method of birth
control/contraception to prevent pregnancy during treatment and for 6 months after
discontinuing study treatment. The definition of effective contraception should be in
agreement with local regulation and based on the judgment of the principal
investigator or a designated associate.
14. Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and
in the judgment of the investigator would make the patient inappropriate for entry
into this study.
15. Current, recent (within 4 weeks of the study treatment administration), or planned
participation in an experimental therapeutic drug study other than this protocol.