Glioblastoma Multiforme
Conditions
Keywords
adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma, adult mixed glioma, recurrent adult brain tumor, adult anaplastic oligodendroglioma, adult oligodendroglioma, adult anaplastic astrocytoma
Brief summary
RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also block the growth of the tumor by blocking blood flow to the tumor. It is not yet known whether bevacizumab together with dasatinib are more effective than a placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme. PURPOSE: This randomized phase I/II trial (Phase I completed) is studying the side effects and best dose of dasatinib when given together with bevacizumab and to see how well it works compared to placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme.
Detailed description
OUTLINE: This is a multicenter, phase I, dose-escalation study (Phase I completed) of dasatinib followed by a phase II randomized study. Patients are grouped according to study (1 vs 2). Patients in the phase II portion are stratified according to age (\> 70 years of age vs ≤ 70 years of age), and ECOG performance status (0 vs 1 or 2). Phase I: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oral dasatinib once or twice daily on days 1-14 until the maximum-tolerated dose (MTD) is determined. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. (Phase I completed) Please see the Arms section for the Phase II treatment regimens. OBJECTIVES: PRIMARY OBJECTIVES: 1. Determine the maximum tolerated dose (MTD) of dasatinib in combination with bevacizumab in high grade glioma patients. (Phase I) 2. To assess the safety and adverse events of the dasatinib in combination with bevacizumab in this patient population. (Phase I) 3. To estimate the efficacy of the bevacizumab combination with dasatinib in recurrent glioblastoma multiforme as measured by progression free survival at six months and compare it with the efficacy of bevacizumab alone. (Phase II) SECONDARY OBJECTIVES: 1. To describe the overall toxicity associated with the dasatinib/bevacizumab combination. (Phase I) 2. To describe any preliminary evidence of antitumor activity. (Phase I) 3. To assess the time to disease progression. (Phase II) 4. To assess the safety and toxicity of the bevacizumab combination with dasatinib in this patient population. (Phase II) 5. To estimate the efficacy of the bevacizumab combination with dasatinib in recurrent glioblastoma multiforme as measured by overall survival time and compare it with the efficacy of bevacizumab alone. (Phase II) 6. To assess the impact of the treatment on the patient's quality of life (QOL) using the overall score from the FACT-Br (Phase II)
Interventions
BIOLOGICALbevacizumab
Given intravenously
DRUGdasatinib
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patient Eligibility: I. Pre-registration: 1\. Central pathology review submission. This review is mandatory prior to registration to confirm eligibility. II. Registration Inclusion Criteria: 1. ≥18 years of age 2. Study 1: Histologic confirmation of grade 3 or 4 glioma, including astrocytoma, oligodendroglioma, and mixed gliomas, as determined by pre-registration central pathology review. 3. Study 2: Histological confirmation of glioblastoma multiforme (grade 4 astrocytoma) as determined by pre-registration central pathology review. NOTE: Variant gliosarcomas are eligible 4. Evidence of tumor progression by MRI or CT scan following RT or following the most recent anti-tumor therapy. Patients who had surgical treatment at recurrence are eligible if there is imaging evidence of disease progression as compared to the first postoperative scan. 5. Bidimensionally measurable or evaluable disease by MRI or CT scan. 6. ECOG Performance Status (PS) 0, 1, or 2. 7. Patient willing to discontinue use of aspirin or medications that inhibit platelet function ≥ 1 week prior to registration. 8. Previous RT and ≥12 weeks since the completion of RT prior to registration. 9. The following laboratory values obtained ≤ 21 days prior to registration. * ANC ≥1500 * PLT ≥100,000 * Hgb \>9.0 g/dL * T. bili ≤1.5 x ULN * SGOT (AST) ≤ 3 x ULN * Creatinine ≤ ULN 10. UPC ratio \<1. NOTE: Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio ≥1.0, 24-hour urine protein must be obtained and the level should be \<1000 mg 11. Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only. 12. Ability to complete questionnaire(s) by themselves or with assistance. 13. Provide informed written consent 14. Willingness to return to enrolling institution for follow-up. 15. Patient willing to provide mandatory tissue samples for research purposes 16. Study 1: Any number of prior chemotherapy regimens for recurrent disease. Study 2: Up to 2 prior chemotherapy regimens with ≤1 regimen for recurrent disease. III.
Exclusion criteria
1. Pregnant women, nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception during this study and for up to 6 months after bevacizumab treatment has ended. NOTE: bevacizumab and dasatinib are investigational agents whose genotoxic effects on the developing fetus and newborn are unknown. 2. Prior intratumoral therapy, stereotactic radiosurgery, or interstitial brachytherapy. EXCEPTION: Separate lesion on MRI which is not part of the previous treatment field, or convincing evidence of recurrent disease, based on biopsy, MRI spectroscopy, or PET scan. 3. Prior treatment with bevacizumab or VEGF-Trap (Aflibercept). 4. Inadequately controlled hypertension (systolic blood pressure of \>150 mmHg or diastolic pressure \>100 mmHg on anti-hypertensive medications). NOTE: Patients with well-controlled hypertension are eligible. 5. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. 6. Immunocompromised patients (other than that related to the use of corticosteroids). NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this study. 7. Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, or prior surgical procedures affecting absorption) that impairs ability to swallow pills. 8. Receiving therapeutic anticoagulation with Warfarin. NOTE: Prophylactic anticoagulation (i.e., low dose warfarin) of venous or arterial access devices is allowed, provided that INR \<1.5. Therapeutic anti-coagulation with low molecular weight heparin is allowed at time of registration. 9. Evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation). 10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. 11. Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm. 12. Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma in-situ of the cervix. Note: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer. 13. History of myocardial infarction or unstable angina ≤6 months prior to registration. 14. New York Heart Association (NYHA) classification II, III or IV congestive heart failure. 15. Core biopsy or other minor surgical procedures ≤7 days prior to registration. Note: Placement of a vascular access device is allowed. 16. Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to registration or anticipation of need for major surgical procedure during the course of the study. 17. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis ≤6 months prior to registration. 18. History of hypertensive crisis or hypertensive encephalopathy. 19. Known hypersensitivity to any of the components of dasatinib or bevacizumab. 20. Serious, non-healing wound, active ulcer, or untreated bone fracture 21. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤6 months prior to registration. 22. Active or recent history of hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤30 days prior to registration. 23. History of stroke or transient ischemic attack (TIA) ≤6 months prior to registration. 24. Any evidence of CNS hemorrhage on baseline CT or MRI 25. Any of the following Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes ≤7 days prior to registration (patients must discontinue drug 7 days prior to starting dasatinib) * Quinidine, procainamide, disopyramide * Amiodarone, sotalol, ibutilide, dofetilide * Erythromycin, clarithromycin * Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide * Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine * Prochlorperazine 26. Diagnosed congenital long QT syndrome 27. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes) 28. Prolonged QTc interval on pre-entry electrocardiogram (\>450 msec) 29. Patients may not have any clinically significant cardiovascular disease including the following: * Myocardial infarction or ventricular tachyarrhythmia within 6 months. * Prolonged QTc ≥ 480 msec (Fridericia correction) * Ejection fraction less than institutional normal * Major conduction abnormality (unless a cardiac pacemaker is present) Note: Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (ECG) to rule out QTc prolongation. The patient may be referred to a cardiologist at the discretion of the principal investigator. Patients with underlying cardiopulmonary dysfunction should be excluded from the study. 30. Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration 31. Known pleural or pericardial effusion of any grade 32. Concomitant use of H2 blockers or proton pump inhibitors that cannot be discontinued or switched to locally acting agents (i.e. famotidine or omeprazole.) 33. Use of the following Enzyme Inducing Anti-Convulsive (EIAC) medications is prohibited ≤ 7 days prior to registration: carbamazepine (Tegretol®, Tegretol XR®, Carbatrol®), phenytoin (Dilantin®, Phenytek®), fosphenytoin (Cerebyx®), phenobarbital, pentobarbital and primidone (Mysoline®). Note: Many antiepileptic drugs induce hepatic enzymes. Because dasatinib is metabolized by hepatic enzymes, patients taking antiepileptic medications that induce hepatic enzymes (EIACs) are ineligible for this trial. To be eligible for this trial, patients taking EIACs must be switched to non-EIACs ≥ 7 days prior to registration. The following agents are not known to affect dasatinib metabolism and are acceptable for use: valproic acid (Depakote®, Depacon®), gabapentin (Neurontin®), lamotrigine (Lamictal®), topiramate (Topamax®), tiagabine (Gabitril®), zonisamide (Zonegran®), levetiracetam (Keppra®), clonazepam (Klonopin®) and clobazam (Frisium®).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I) | 14 days | The Maximum Tolerated Dose (MTD) will be based on the assessment of dose-limiting toxicities (DLT) during the first 4 weeks of treatment only (i.e., following the first 2 treatment cycles), and will be defined as the dose at which fewer than one-third of patients experience a DLT to study treatment. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with the next higher dose having at least 2 out of 3 or 2 out of 6 patients encountering DLT.\> Three patients will be treated at each dose level, and can be enrolled simultaneously. If one DLT is encountered, an additional 3 patients will be added to that dose level. If at any point two DLTs are encountered within a given dose level, then the MTD has been exceeded and if only three patients have been treated at the next lower dose three more patients are treated at the next lower dose. The number of patients who developed DLTs are reported here by dose level, with the MTD reported in the statistical analysis section. |
| Progression-free Survival at 6 Months (PFS6) (Phase II) | 6 months | The primary endpoint is the proportion of patients alive and progression-free 6 months after study treatment initiation (PFS6). All eligible consented patients that received treatment will be considered evaluable. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred. PFS6 is defined as the time from start of study therapy to the date of first observation of disease progression or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The PFS6 will be estimated as the number of evaluable patients progression free and still alive at 6 months divided by the total number of evaluable patients. The confidence interval will be calculated according to the Clopper-Pearson Method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-disease Progression (Phase II) | Up to 3 years | Time-to-disease progression is defined as the time from start of study therapy to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death unless there is documented evidence that no progression occurred before death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy or date last known to be alive, whichever is later. Patients who are still alive and have not progressed will be censored for progression at the time of the last tumor assessment. Patients who experience major treatment violations will be censored for progression on the date the treatment violation occurred. The time-to-progression distribution will be estimated using the Kaplan-Meier method. |
| Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II) | Up to 3 years | Adverse events were collected systematically at the end of each cycle and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Events are scored as: 1=Mild symptoms, 2= Moderate, 3=Severe, 4=Life-threatening, and 5=Death. The number of patients reporting a grade 3 or higher event regardless of attribution are summarized here. A complete list of all adverse events reported during treatment can be found in the Adverse Events Section. |
| Objective Response (Phase II) | Up to 3 years | Objective response to treatment will be determined by the results of neurological exam and the MRI and/or CT measurement of the tumor at each evaluation as is used for all NCCTG neuro-oncology trials. The percentage of patients in each response category will be summarized, 95% confidence intervals calculated, and rates between the 2 arms will be compared using a Fisher's Exact test. For bi-dimensionally measurable disease, CR: total disappearance of all tumor and that patients be on no corticosteroids or on only adrenal replacement maintenance; PR: ≥ 50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions, and stable or decreasing steroid dosing; PD: \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions; REGR: unequivocal reduction in extent of contrast-enhancement, or a decrease in mass effect, no new lesions (for evaluable disease); SD: failure to qualify for CR, PR,REGR or PD. |
| Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Baseline to cycle 10 (20 weeks). | FACT-Br questionnaires were used to assess QOL at every other cycle of treatment (prior to cycles 3, 5, 7, etc.). FACT-Br includes 50 questions used to assess patients' self-assessment in 4 broad categories: Physical, Social/Family, Emotional, and Function Well-being. Scores range from 0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very Much. Higher scores can be interpreted as having higher quality of life. The scores for all 50 questions were summed to give a total score per patient per cycle. Therefore the possible range is from 0 to 200. Below is the reported mean and standard deviation for patients at baseline and during cycles 2, 4, 6, 8, and 10. |
| Overall Survival (Phase II) | Up to 3 years | Survival time is defined to be the length of time from start of study therapy to death due to any cause. All patients meeting the eligibility criteria that have signed a consent form and begun treatment will be considered evaluable for estimation of the survival distribution. The distribution of overall survival for both arms of the study will be estimated using the Kaplan-Meier method, and be compared using log-rank tests. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Patients receive (either: 5 or 10 mg/kg) bevacizumab IV over 90 minutes on Day 1 and oral dasatinib (either: 50, 70, or 100 mg) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | 16 |
| Phase II: Arm A (Bevacizumab + Dasatinib) Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | 83 |
| Phase II: Arm B (Bevacizumab + Placebo) Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | 38 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase II | Ineligible | 0 | 0 | 0 | 0 | 1 | 1 |
| Phase II | Withdrawal by Subject | 0 | 0 | 0 | 0 | 4 | 1 |
Baseline characteristics
| Characteristic | Phase I | Phase II: Arm A (Bevacizumab + Dasatinib) | Phase II: Arm B (Bevacizumab + Placebo) | Total |
|---|---|---|---|---|
| Age, Continuous | 46.5 years | 58 years | 56.5 years | 57 years |
| Region of Enrollment United States | 16 Participants | 83 Participants | 38 Participants | 137 Participants |
| Sex: Female, Male Female | 3 Participants | 28 Participants | 16 Participants | 47 Participants |
| Sex: Female, Male Male | 13 Participants | 55 Participants | 22 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 3 / 3 | 6 / 6 | 83 / 84 | 39 / 39 |
| serious Total, serious adverse events | 2 / 3 | 1 / 4 | 2 / 3 | 1 / 6 | 32 / 84 | 18 / 39 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I)
The Maximum Tolerated Dose (MTD) will be based on the assessment of dose-limiting toxicities (DLT) during the first 4 weeks of treatment only (i.e., following the first 2 treatment cycles), and will be defined as the dose at which fewer than one-third of patients experience a DLT to study treatment. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with the next higher dose having at least 2 out of 3 or 2 out of 6 patients encountering DLT.\> Three patients will be treated at each dose level, and can be enrolled simultaneously. If one DLT is encountered, an additional 3 patients will be added to that dose level. If at any point two DLTs are encountered within a given dose level, then the MTD has been exceeded and if only three patients have been treated at the next lower dose three more patients are treated at the next lower dose. The number of patients who developed DLTs are reported here by dose level, with the MTD reported in the statistical analysis section.
Time frame: 14 days
Population: Adverse event information is available for 4 patients on study 1 dose level 1 (with 1 being a MTD replacement due to disease progression prior to completing cycles 1 and 2).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I : Dose Level 0 | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I) | 0 participants who developed DLTs |
| Phase I : Dose Level 1 | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I) | 0 participants who developed DLTs |
| Phase I : Dose Level 2 | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I) | 0 participants who developed DLTs |
| Phase I : Dose Level 3 Cohort 1 | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I) | 0 participants who developed DLTs |
| Phase I: Dose Level 3 Cohort 2 | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I) | 1 participants who developed DLTs |
Primary
Progression-free Survival at 6 Months (PFS6) (Phase II)
The primary endpoint is the proportion of patients alive and progression-free 6 months after study treatment initiation (PFS6). All eligible consented patients that received treatment will be considered evaluable. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred. PFS6 is defined as the time from start of study therapy to the date of first observation of disease progression or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The PFS6 will be estimated as the number of evaluable patients progression free and still alive at 6 months divided by the total number of evaluable patients. The confidence interval will be calculated according to the Clopper-Pearson Method.
Time frame: 6 months
Population: All patients that received treatment and were eligible for assessment were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I : Dose Level 0 | Progression-free Survival at 6 Months (PFS6) (Phase II) | 0.29 proportion of participants |
| Phase I : Dose Level 1 | Progression-free Survival at 6 Months (PFS6) (Phase II) | 0.18 proportion of participants |
p-value: 0.2295% CI: [-0.052, 0.262]Chi-squared, Corrected
Secondary
Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II)
Adverse events were collected systematically at the end of each cycle and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Events are scored as: 1=Mild symptoms, 2= Moderate, 3=Severe, 4=Life-threatening, and 5=Death. The number of patients reporting a grade 3 or higher event regardless of attribution are summarized here. A complete list of all adverse events reported during treatment can be found in the Adverse Events Section.
Time frame: Up to 3 years
Population: All Phase II patients treated and evaluated for adverse events are included in this Phase II endpoint analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I : Dose Level 0 | Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II) | Grade 3 Adverse Event | 42 participants |
| Phase I : Dose Level 0 | Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II) | Grade 4 Adverse Event | 8 participants |
| Phase I : Dose Level 0 | Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II) | Grade 5 Adverse Event | 5 participants |
| Phase I : Dose Level 1 | Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II) | Grade 4 Adverse Event | 2 participants |
| Phase I : Dose Level 1 | Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II) | Grade 3 Adverse Event | 23 participants |
| Phase I : Dose Level 1 | Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II) | Grade 5 Adverse Event | 3 participants |
Secondary
Objective Response (Phase II)
Objective response to treatment will be determined by the results of neurological exam and the MRI and/or CT measurement of the tumor at each evaluation as is used for all NCCTG neuro-oncology trials. The percentage of patients in each response category will be summarized, 95% confidence intervals calculated, and rates between the 2 arms will be compared using a Fisher's Exact test. For bi-dimensionally measurable disease, CR: total disappearance of all tumor and that patients be on no corticosteroids or on only adrenal replacement maintenance; PR: ≥ 50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions, and stable or decreasing steroid dosing; PD: \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions; REGR: unequivocal reduction in extent of contrast-enhancement, or a decrease in mass effect, no new lesions (for evaluable disease); SD: failure to qualify for CR, PR,REGR or PD.
Time frame: Up to 3 years
Population: All eligible Phase II patients are included in this Phase II endpoint analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I : Dose Level 0 | Objective Response (Phase II) | REGR | 10.8 percentage of participants |
| Phase I : Dose Level 0 | Objective Response (Phase II) | CR | 2.4 percentage of participants |
| Phase I : Dose Level 0 | Objective Response (Phase II) | PD | 12.0 percentage of participants |
| Phase I : Dose Level 0 | Objective Response (Phase II) | SD | 57.8 percentage of participants |
| Phase I : Dose Level 0 | Objective Response (Phase II) | Missing/Unknown | 14.5 percentage of participants |
| Phase I : Dose Level 0 | Objective Response (Phase II) | PR | 2.4 percentage of participants |
| Phase I : Dose Level 1 | Objective Response (Phase II) | Missing/Unknown | 10.5 percentage of participants |
| Phase I : Dose Level 1 | Objective Response (Phase II) | SD | 57.9 percentage of participants |
| Phase I : Dose Level 1 | Objective Response (Phase II) | CR | 2.6 percentage of participants |
| Phase I : Dose Level 1 | Objective Response (Phase II) | REGR | 18.4 percentage of participants |
| Phase I : Dose Level 1 | Objective Response (Phase II) | PD | 5.3 percentage of participants |
| Phase I : Dose Level 1 | Objective Response (Phase II) | PR | 5.3 percentage of participants |
p-value: 0.6325Fisher Exact
Secondary
Overall Survival (Phase II)
Survival time is defined to be the length of time from start of study therapy to death due to any cause. All patients meeting the eligibility criteria that have signed a consent form and begun treatment will be considered evaluable for estimation of the survival distribution. The distribution of overall survival for both arms of the study will be estimated using the Kaplan-Meier method, and be compared using log-rank tests.
Time frame: Up to 3 years
Population: All eligible Phase II patients are included in this Phase II endpoint analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I : Dose Level 0 | Overall Survival (Phase II) | 7.3 months |
| Phase I : Dose Level 1 | Overall Survival (Phase II) | 7.9 months |
p-value: 0.795% CI: [0.61, 1.4]Kaplan Meier
Secondary
Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II)
FACT-Br questionnaires were used to assess QOL at every other cycle of treatment (prior to cycles 3, 5, 7, etc.). FACT-Br includes 50 questions used to assess patients' self-assessment in 4 broad categories: Physical, Social/Family, Emotional, and Function Well-being. Scores range from 0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very Much. Higher scores can be interpreted as having higher quality of life. The scores for all 50 questions were summed to give a total score per patient per cycle. Therefore the possible range is from 0 to 200. Below is the reported mean and standard deviation for patients at baseline and during cycles 2, 4, 6, 8, and 10.
Time frame: Baseline to cycle 10 (20 weeks).
Population: All Phase II patients that began treatment and submitted at least one FACT-Br questionnaire were included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I : Dose Level 0 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 8 | 142.3 units on a scale | Standard Deviation 30.2 |
| Phase I : Dose Level 0 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 4 | 137.6 units on a scale | Standard Deviation 30.1 |
| Phase I : Dose Level 0 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 6 | 140.1 units on a scale | Standard Deviation 29 |
| Phase I : Dose Level 0 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle10 | 142.1 units on a scale | Standard Deviation 34.9 |
| Phase I : Dose Level 0 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 0 | 139.5 units on a scale | Standard Deviation 26.2 |
| Phase I : Dose Level 0 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 2 | 131.2 units on a scale | Standard Deviation 27.9 |
| Phase I : Dose Level 1 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 0 | 138.3 units on a scale | Standard Deviation 22.4 |
| Phase I : Dose Level 1 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 2 | 133.5 units on a scale | Standard Deviation 23.5 |
| Phase I : Dose Level 1 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle10 | 149.3 units on a scale | Standard Deviation 34.4 |
| Phase I : Dose Level 1 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 4 | 137.4 units on a scale | Standard Deviation 23.1 |
| Phase I : Dose Level 1 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 6 | 137.7 units on a scale | Standard Deviation 25.7 |
| Phase I : Dose Level 1 | Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) | Cycle 8 | 142.8 units on a scale | Standard Deviation 31.1 |
p-value: 0.96Mixed Models Analysis
Secondary
Time-to-disease Progression (Phase II)
Time-to-disease progression is defined as the time from start of study therapy to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death unless there is documented evidence that no progression occurred before death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy or date last known to be alive, whichever is later. Patients who are still alive and have not progressed will be censored for progression at the time of the last tumor assessment. Patients who experience major treatment violations will be censored for progression on the date the treatment violation occurred. The time-to-progression distribution will be estimated using the Kaplan-Meier method.
Time frame: Up to 3 years
Population: All eligible Phase II patients are included in this Phase II endpoint analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I : Dose Level 0 | Time-to-disease Progression (Phase II) | 3.3 months |
| Phase I : Dose Level 1 | Time-to-disease Progression (Phase II) | 3.5 months |
p-value: 0.5295% CI: [0.76, 1.7]Kaplan Meier