Astrocytoma, Glioblastoma Multiforme
Conditions
Keywords
Open label, Imatinib mesylate, hydroxyurea, temozolomide, resistant, protein tyrosine kinases, adenocarcinoma, glioblastoma multiforme, astrocytoma, brain tumor, brain cancer
Brief summary
This is a Phase III study comparing Imatinib mesylate and hydroxyurea combination therapy with hydroxyurea monotherapy in patients with temozolomide resistant progressive glioblastoma.
Interventions
DRUGImatinib mesylate
Imatinib was supplied as 100 mg and 400 mg tablets packaged in polyethylene bottles.
DRUGHydroxyurea
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent prior to initiation of any study procedure. * Patients \>= 18 years of age. * Histological confirmed diagnosis of glioblastoma multiforme / astrocytoma World Health Organization (WHO) grade IV by a reference pathologist * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2. * Adequate hepatic, renal and bone marrow function as defined by the following: total bilirubin \< 1.5 x Upper Limit of Normal (ULN), ALT and AST \< 2.5 x ULN, creatinine \< 1.5 x ULN, absolute neutrophil count \> 1.5 x109/L, platelets \> 100 x109/L and hemoglobin \> 10 g/dL. * Female patients of childbearing potential with a negative pregnancy test within 7 days of initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential who agree to employ an effective barrier method of birth control throughout the study, and for up to 3 months following discontinuation of study drug. * Life expectancy of \>3 months. * MRI available every 6 weeks for disease management * No intercerebral inflammation * Irradiation therapy 54 to 62 gy finished or less according to national standard * Chemotherapy at least 1 temozolomide containing regimen finished, no established chemotherapy regiment available and progression under chemotherapy or in between 6 months following the last chemotherapy. * Leucocytes \> 2.500/µl, to be controlled once a week * Thrombocytes \> 80.000/µl, to be controlled once a week * Ensured compliance * Patients who had a second or third resection after disease progression cannot be included earlier than 2 weeks following the resection. MRI should be performed not later than 72 h post operation. If patients are to be included later than 4 weeks after the resection, a new baseline MRI must be performed.
Exclusion criteria
* Female patients who are pregnant or breast-feeding. * Patients who have been treated with any investigational agent(s) within 28 days of the first day of administration of study drug. * Patients with uncontrolled medical disease such as diabetes mellitus, thyroid dysfunction, neuropsychiatric disorders, infection, angina or Grade 3 or 4 cardiac problems as defined by the New York Heart Association Criteria. * Patients with other malignant disorders. * Patient with acute or known chronic liver disease (i.e., chronic active hepatitis, cirrhosis). * Patients who are known to be HIV positive (no specific tests are required for confirmation of eligibility). * Expected incompliance according to treatment, treatment diary and examination schedule * Not confirmed histological diagnosis glioblastoma multiforme/astrocytoma WHO grade IV * Other drugs with potential cytostatic main or side effect * No or inadequate chemotherapy or irradiation therapy * Patients without hematological recovery after previous chemotherapy who have been treated with Chemotherapy within 28 days of the first day of administration of study drug. Other protocol-specific inclusion /
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Progression Free Survival (PFS) During the Study Duration | 6 months -1 year | PFS was defined as the time from the date of randomization to the date of the first documented progression according to the MacDonald criteria, or death due to any cause. MacDonald criteria are standard criteria in neurooncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | 6 months - 1 year | National Cancer Institute (NCI)/ National Institute of Health (NIH) provides a grading (severity) scale for each AE term. Grade 3 refers to severe AE and Grade 4 refers to life-threatening or disabling AE. According to FDA 21CFR 314.80, a serious adverse event (SAE) is described as any adverse event that leads to death, is life threatening ( NIH criteria Grade 4), causes or prolongs hospitalization, results in a congenital anomaly, or any other important medical event not described above. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Imatinib Mesylate + Hydroxyurea (HU) Imatinib was supplied as 100 mg and 400 mg tablets. Patients in the combination arm were instructed to take a daily oral imatinib dose of 600 mg (600 mg at lunch time) and a daily oral hydroxyurea (HU) dose of 1000 mg (500 mg twice daily; in the morning and at bed time). Every 6 weeks after randomization based on assessment of therapeutic response, either patients continued with above mentioned dosing regimen or switched to receive a daily dose of 800 mg imatinib with 1000 mg HU. Patients were instructed to split the intake, taking 400 mg imatinib with 500 mg HU in the morning, then the same in the evening. | 120 |
| Hydroxyurea Alone 1500 mg/day of HU given as 500 mg 3 times daily. Every 6 weeks after randomization and based on assessment of therapeutic response, the patients were either switched to combination arm or continued in monotherapy arm of hydroxyurea. | 120 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 0 | 2 |
| Overall Study | Adverse Event | 18 | 20 |
| Overall Study | Death | 5 | 13 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Study drug no longer required | 5 | 3 |
| Overall Study | Suspected progression of disease | 44 | 30 |
| Overall Study | Unsatisfactory therapeutic effect | 25 | 26 |
| Overall Study | Withdrawal by Subject | 14 | 10 |
Baseline characteristics
| Characteristic | Imatinib Mesylate + Hydroxyurea (HU) | Hydroxyurea Alone | Total |
|---|---|---|---|
| Age Continuous | 52.1 years STANDARD_DEVIATION 11.3 | 50.2 years STANDARD_DEVIATION 11.4 | 51.2 years STANDARD_DEVIATION 11.4 |
| Sex: Female, Male Female | 50 Participants | 38 Participants | 88 Participants |
| Sex: Female, Male Male | 70 Participants | 82 Participants | 152 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 104 / 118 | 80 / 118 | 65 / 85 |
| serious Total, serious adverse events | 64 / 118 | 46 / 118 | 49 / 85 |
Outcome results
Primary
Percentage of Participants With Progression Free Survival (PFS) During the Study Duration
PFS was defined as the time from the date of randomization to the date of the first documented progression according to the MacDonald criteria, or death due to any cause. MacDonald criteria are standard criteria in neurooncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator).
Time frame: 6 months -1 year
Population: The ITT population consists of all randomized patients, analyzed according to their randomized treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib Mesylate + Hydroxyurea (HU) | Percentage of Participants With Progression Free Survival (PFS) During the Study Duration | 6 months | 5.3 Percentage of Participants |
| Imatinib Mesylate + Hydroxyurea (HU) | Percentage of Participants With Progression Free Survival (PFS) During the Study Duration | 12 months | 2.1 Percentage of Participants |
| Hydroxyurea Alone | Percentage of Participants With Progression Free Survival (PFS) During the Study Duration | 6 months | 6.6 Percentage of Participants |
| Hydroxyurea Alone | Percentage of Participants With Progression Free Survival (PFS) During the Study Duration | 12 months | 2.1 Percentage of Participants |
Secondary
Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations
National Cancer Institute (NCI)/ National Institute of Health (NIH) provides a grading (severity) scale for each AE term. Grade 3 refers to severe AE and Grade 4 refers to life-threatening or disabling AE. According to FDA 21CFR 314.80, a serious adverse event (SAE) is described as any adverse event that leads to death, is life threatening ( NIH criteria Grade 4), causes or prolongs hospitalization, results in a congenital anomaly, or any other important medical event not described above.
Time frame: 6 months - 1 year
Population: The safety population consisted of randomized patients with at least one dose of randomized medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib Mesylate + Hydroxyurea (HU) | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Leading to dose adjustment or interruption | 6 Participants |
| Imatinib Mesylate + Hydroxyurea (HU) | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Deaths | 84 Participants |
| Imatinib Mesylate + Hydroxyurea (HU) | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Death due to disease progression | 76 Participants |
| Imatinib Mesylate + Hydroxyurea (HU) | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Serious Adverse Events (SAEs) | 64 Participants |
| Imatinib Mesylate + Hydroxyurea (HU) | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | NCI/NIH Grade 3 (severe) or 4 (life threatening) | 54 Participants |
| Imatinib Mesylate + Hydroxyurea (HU) | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Suspected to be drug-related | 12 Participants |
| Imatinib Mesylate + Hydroxyurea (HU) | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Leading to permanent discontinuation | 9 Participants |
| Hydroxyurea Alone | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Leading to dose adjustment or interruption | 16 Participants |
| Hydroxyurea Alone | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | NCI/NIH Grade 3 (severe) or 4 (life threatening) | 64 Participants |
| Hydroxyurea Alone | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Deaths | 91 Participants |
| Hydroxyurea Alone | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Leading to permanent discontinuation | 13 Participants |
| Hydroxyurea Alone | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Death due to disease progression | 77 Participants |
| Hydroxyurea Alone | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Suspected to be drug-related | 12 Participants |
| Hydroxyurea Alone | Number of Participants With Death, Other Serious or Clinically Significant Adverse Events (AEs) or Related Discontinuations | Serious Adverse Events (SAEs) | 79 Participants |