1. Histopathological diagnosis of glioblastoma (= WHO grade IV glioma of the central
nervous system); both "de novo" and "secondary" glioblastoma are eligible;
2. Diagnosis of glioma recurrence or progression following prior treatment with
surgery, radiation therapy and alkylating chemotherapy (defined as significant
[according to the investigators individual assessment] growth or recurrence of the
glioblastoma demonstrated on sequential Gd-MRI before the time of recruitment).
3. The following disease characteristics should be present:
1. Presence of a measurable tumor lesion that is characterized by gadolinium
enhancement on T1-MRI of the brain (with a longest diameter of > 10 mm);
2. Enhancing characteristics of the glioblastoma as compared to the normal brain
on 18F-FET PET (patients with a non-enhancing lesion are not eligible);
3. No evidence of clinically meaningful spontaneous intra-tumoral hemorrhage on
baseline MRI-imaging or in the prior disease history;
4. No contraindication for evaluation by Gd-MRI or 18F-FET PET of the brain;
5. Archival glioma tissue must be available for collection and storage in a centralized
tumor bank;
6. An interval of at least 3 months (12 weeks) after the end of prior radiation
therapy; and an interval of at least 4 weeks after the last administration of
cytotoxic drug treatment (6 weeks in case of administration of a nitrosureum or
mitomycin C); and an interval of at least 4 weeks after the last administration of
any other kind of anti glioblastoma treatment;
7. A stable dose of corticosteroids for at least 14 days before the initiation of study
treatment with axitinib;
8. WHO performance status of 0 or 1;
9. Life expectancy of ≥12 weeks;
10. Male or female, 18 years of age or older;
11. Resolution of all acute toxic effects of prior systemic therapy, radiotherapy or
surgical procedure to NCI CTCAEv3.0 grade 0 or 1 or back to baseline except for
alopecia or hypothyroidism;
12. Adequate organ function as defined by the following criteria:
- - Total serum bilirubin < 1.5 x ULN (patients with Gilbert's disease exempt)
- AST and ALT < 2.5 x upper limit of normal (ULN);
- Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min.
- - Absolute neutrophil count (ANC) > 1500/mm³ without growth factor support.
- - Platelets > 75 000 cells/mm³
- Hemoglobin ≥9 g/dL (which may be obtained by transfusion or growth factor
support)
- Urinary protein <1+ by urine dipstick.
If dipstick is ≥1+ then a 24-hour urine
collection should be done and the patient may enter only if urinary protein is
<2 grams per 24 hours. 13. Women of childbearing potential must have a negative serum or urine pregnancy test
within 3 days prior to treatment.;
14. Female patients must be surgically sterile or be postmenopausal, or must agree to
use effective contraception measures during the period of therapy which should be
continued for 4 weeks after the last dose of axitinib. All female patients with
reproductive potential must have a negative pregnancy test (serum or urine) prior to
enrollment. Male patients must be surgically sterile or must agree to use effective
contraception during the period of therapy. The definition of effective
contraception will be based on the judgment of the principal investigator or a
designated associate;
15. No previous treatment on an axitinib trial;
16. No previous treatment with a VEGF or VEGFR-targeted drug (including, but not limited
to bevacizumab, aflibercept, cediranib, sorafenib, sunitinib, XL184, and pazopanib);
17. No gastrointestinal abnormalities including:
1. Inability to take oral medication.
2. Requirement for intravenous alimentation.
3. Prior surgical procedures affecting absorption including gastric resection.
4. Treatment for active peptic ulcer disease in the past 6 months.
5. Malabsorption syndromes.
6. 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;
18. No evidence of preexisting 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;
19. No concurrent treatment:
1. In another therapeutic clinical trial;
2. With a drug having pro-arrhythmic potential;
3. With enzyme inducing anti-epileptic drugs (EIAED) within 14 days before dosing
with axitinib (e.g. carbamazepine, phenobarbital, phenytoin);
20. No 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).
21. No 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).
22. No 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.
23. No active seizure disorder or evidence of brain metastases, spinal cord compression,
or carcinomatous meningitis.
24. No myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure or any unstable arrhythmia,
cerebrovascular accident or transient ischemic attack, within the 12 months prior to
study drug administration. No current or recent (within 1 month) use of a
thrombolytic agent or a thrombo-embolic event;
25. No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness;
26. No serious uncontrolled medical disorder or active infection that would impair their
ability to receive study treatment;
27. No history of a malignancy (other than glioma) except those treated with curative
intent for skin cancer (other than melanoma) or in situ breast or cervical cancer or
those treated with curative intent for any other cancer with no evidence of disease
for 5 years;
28. No major surgical procedure, open biopsy, or significant traumatic injury within 4
weeks of treatment. (Also excluded are patient with fine needle aspirations within 7
days of treatment);
29. No pregnancy or breastfeeding;
30. No history of hemoptysis > ½ tsp of bright red blood per day within past 1 week;
31. No other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that would impart, in the judgment of the investigator, excess risk
associated with study participation or study drug administration, or which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study;
32. No dementia or significantly altered mental status that would prohibit the
understanding or rendering of informed consent and compliance with the requirements
of this protocol;
33. Signed and dated informed consent document indicating that the patient (or legally
acceptable representative) has been informed of all the pertinent aspects of the
trial prior to enrollment;
34. Willingness and ability to comply with scheduled visits, treatment plans and
laboratory tests and other study procedures.
