Axitinib In Recurrent Glioblastoma (Axig)

1.Trial Objectives and Endpoints

1.1Primary objective and endpoint

1.1.1Axitinib treatment-arm

  • Objective
/
  • Endpoint

  • To estimate the anti-tumor effect of axitinib as a single therapeutic agent for the treatment of glioblastoma patients at the time of recurrence/progression following prior surgery, radiation and alkylating chemotherapy
/
  • The percentage of patients who are alive and free-from progression at 6-month (24 weeks) following the date of randomisation (6-monthPFS%)

1.1.2Control-arm

  • Objective
/
  • Endpoint

  • To serve as a contemporary control cohort for the axitinib-arm of the study.
/
  • The percentage of patients who are alive and free-from progression at 6-month (24 weeks) following the date of randomisation (6-monthPFS%)

1.2Secondary objectives and endpoints

1.2.1Axitinib treatment-arm

  • Objective
/
  • Endpoint

  • To document the safety and tolerability of axitinib treatment
/
  • Incidence, characteristics, severity, and causality of adverse events during the study period; categorized according to the CTCAEv4.0

  • Axitinib treatment disposition
/
  • Descriptive statistics will be used to summarize treatment administration, and treatment compliance

  • Corticosteroid use
/
  • Descriptive analysis will be used to summarize the corticosteroid treatment disposition

  • Tumor response
/
  • Tumor response based on MRI assessment, categorized according to the RANO criteria;
  • Descriptive report on the characteristics of tumor response on 18F-FET PET

  • Survival
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  • Median, and 12-months% PFS and OS according to Kaplan-Meier survival estimates.

1.2.2Control-arm

  • Objective
/
  • Endpoint

  • To document the type of therapy administered following randomization (the nature of which will be at the discretion of the treating physician)
/
  • Descriptive statistics will be used to summarize the type of treatment allocation

  • Survival
/
  • Median, and 12-months% PFS and OS according to Kaplan-Meier survival estimates.

1.3Exploratory objectives

  • To establish a bio-bank containing the glioma tissues and blood from the patients treated in this study. Availability glioma tissue for tumor banking will be part of the patient eligibility criteria.
  • Archival glioma material will be collected and stored for review histopathology and molecular-genetic analysis to be executed in a companion translational study. Molecular analysis may include but will not necessarily be restricted to following molecular-genetic targets: PDGF, PDGFR, VEGF, VEGFR, p53, EGFR gene copy number, IDH1 and IDH2, and MGMT promoter methylation status).
  • An exploratory correlation of molecular-genetic characteristics of the glioma treated in this study with the results of neuro-immaging, and survival will be performed.
  • The execution of the companion translational study will be decided following the completion of the clinical study and will be dependent on the obtained clinical results.

2. Patient Selection Criteria

The following subject eligibility criteria are designed to select subjects for whom protocol treatment is considered appropriate. All relevant medical and non-medical conditions should be taken into consideration when deciding whether this protocol is suitable for a particular subject.

Patients must meet all of the following recruitment criteria to be eligible for enrollment into the trial:

  1. Histopathological diagnosis of glioblastoma (= WHO grade IV glioma of the central nervous system); both patients with “de novo” and “secondary” glioblastoma are eligible;
  2. Diagnosis of glioblastoma recurrence or progression following prior treatment with surgery, radiation therapy and temozolomide chemotherapy (defined as significant [according to the investigators individual assessment] growth or recurrence of the glioblastoma on sequential Gd-MRI of the brain);
  3. The following disease characteristics should be present:
  4. 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);
  5. No evidence of clinically relevant spontaneous intra-tumor hemorrhage on baseline MRI-imaging or in the prior disease history;
  6. No contraindication for evaluation by gadolinium enhanced MRI of the brain;
  7. Archival glioma tissue must be available for collection and storage in a centralized tumor bank;
  8. An interval of at least 4 months (16 weeks) after the end of radiation therapy for glioblastoma unless progression is confirmed on an MRI of the brain obtained 4 week after the first observation of progression; and an interval of at least 4 weeks after the last administration of temozolomide;
  9. A stable dose of corticosteroids for at least 14 days before the initiation of study treatment with axitinib;
  10. WHO performance status of 0, 1, or 2;
  11. Life expectancy of ≥12 weeks;
  12. Male or female, 18 years of age or older;
  13. Resolution of all acute toxic effects of prior surgical procedures, radiotherapy and temozolomide to NCI CTCAEv4.0 grade 0 or 1 except for alopecia;
  14. Adequate organ function as defined by the following criteria:
  • Total serum bilirubin < 1.5 x ULN (patients with Gilbert’s disease exempt who should have bilirubin < 2x ULN)
  • 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
  • FT4 hormone levels within normal range
  1. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.;
  2. 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;
  3. No prior treatment on an axitinib trial;
  4. No prior treatment with a VEGF or VEGFR-targeted drug (including, but not limited to bevacizumab, aflibercept, cediranib, sorafenib, sunitinib, XL184, and pazopanib);
  5. No prior treatment with a cytotoxic chemotherapy at the exception of temozolomide (administered either concomitant with radiation therapy, following radiation therapy, or at the time of recurrence);
  6. No gastrointestinal abnormalities including:
  7. Inability to take oral medication.
  8. Requirement for intravenous alimentation.
  9. Prior surgical procedures affecting absorption including gastric resection.
  10. Treatment for active peptic ulcer disease in the past 6 months.
  11. Malabsorption syndromes.
  12. 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;
  13. 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;
  14. No concurrent treatment:
  15. In another therapeutic clinical trial;
  16. With a drug having pro-arrhythmic potential;
  17. With enzyme inducing anti-epileptic drugs (EIAED) within 14 days before dosing with axitinib (e.g. carbamazepine, phenobarbital, phenytoin);
  18. 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).
  19. 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).
  20. 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.
  21. No active uncontrolled seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
  22. No myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure or any unstable arrhythmia, cerebrovascular accident (ischemic or hemorrhagic) 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;
  23. No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness;
  24. No serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment;
  25. 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;
  26. 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);
  27. No pregnancy or breastfeeding;
  28. No history of hemoptysis > ½ tsp of bright red blood per day within past 1 week;
  29. 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;
  30. 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;
  31. 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;
  32. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures.