| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
• Patients with recurrent central nervous system glioblastoma (histologically confirmed WHO grade IV glioma), at documented recurrence/progression following prior treatment with surgery, radiation therapy and alkylating chemotherapy.
• No concomitant treatment with enzyme inducing anti-epileptic drugs (EIAED)
|
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To estimate the anti-tumor effect of axitinib as a mono-therapy (Arm A, cohort A2) or the combination of axtinib plus lomustine for the treatment of glioblastoma patients at the time of recurrence/progression following prior surgery, radiation and temozolomide chemotherapy |
|
| E.2.2 | Secondary objectives of the trial |
•To document the safety and tolerability of axitinib treatment
•Axitinib and Lomustine treatment disposition
•Corticosteroid use
•Tumor response
•Survival |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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:
a. 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);
b. No evidence of clinically relevant spontaneous intra-tumor hemorrhage on baseline MRI-imaging or in the prior disease history;
4. No contraindication for evaluation by gadolinium enhanced MRI 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 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;
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, 1, or 2;
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 surgical procedures, radiotherapy and temozolomide to NCI CTCAEv4.0 grade 0 or 1 except for alopecia;
12. 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
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. 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;
16. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures.
|
|
| E.4 | Principal exclusion criteria |
1. No prior treatment on an axitinib trial;
2. No prior treatment with a VEGF or VEGFR-targeted drug (including, but not limited to bevacizumab, aflibercept, cediranib, sorafenib, sunitinib, XL184, and pazopanib);
3. 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);
4. No gastrointestinal abnormalities including:
• Inability to take oral medication.
• Requirement for intravenous alimentation.
• Prior surgical procedures affecting absorption including gastric resection.
• Treatment for active peptic ulcer disease in the past 6 months.
• Malabsorption syndromes.
• 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;
5. 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;
6. No concurrent treatment:
a. In another therapeutic clinical trial;
b. With a drug having pro-arrhythmic potential;
c. With enzyme inducing anti-epileptic drugs (EIAED) within 14 days before dosing with axitinib (e.g. carbamazepine, phenobarbital, phenytoin);
7. 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).
8. 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).
9. 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.
10. No active uncontrolled seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
11. 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;
12. No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness;
13. No serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment;
14. 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;
15. 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);
16. No pregnancy or breastfeeding;
17. No history of hemoptysis > ½ tsp of bright red blood per day within past 1 week;
18. 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;
19. 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;
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- The percentage of patients who are alive and free-from progression at 6-month (24 weeks) following the date of randomization (6-month PFS%).
- Incidence, characteristics, severity, and causality of adverse events during the study period; categorized according to the CTCAEv4.0.
- Descriptive statistics will be used to summarize treatment administration, and treatment compliance.
- Descriptive analysis will be used to summarize the corticosteroid treatment disposition.
- Tumor response based on MRI assessment, categorized according to the RANO criteria; Descriptive report on the characteristics of tumor response on 18F-FET PET.
- Median, and 12-months% PFS and OS according to Kaplan-Meier survival estimates.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6-months following the randomization of the subject |
|
| E.5.2 | Secondary end point(s) |
• Safety, reported according to the CTCAEv4.0
• Axitinib (and lomustine) treatment disposition
• Document corticosteroid use
• Tumor response according to the RANO criteria
• Tumor response assessment by 18F-FET PET
• Estimate TTP, and OS
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety and medication use: continuously throughout the trial
Tumor response: every 6-weeks |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of study: 6 weeks after the study medication administration to the last patient on study drug, or death of the last patient in this trial (whatever comes first). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
