Glioblastoma
Conditions
Keywords
adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma, recurrent adult brain tumor
Brief summary
RATIONALE: Cediranib Maleate and gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether cediranib maleate given together with gefitinib is more effective than cediranib maleate given alone in treating patients with recurrent or progressive glioblastoma. PURPOSE: This randomized phase II trial is studying the side effects of giving cediranib maleate together with gefitinib and to see how well it works compared with giving cediranib maleate together with a placebo in treating patients with recurrent or progressive glioblastoma.
Detailed description
OBJECTIVES: * To compare progression-free survival, overall survival, radiological response, and safety and tolerability of cediranib maleate in combination with gefitinib versus cediranib maleate in combination with a placebo in patients with recurrent or progressive glioblastoma following standard front-line treatment. OUTLINE: This is a multicenter study. Patients receive cediranib maleate and gefitinib or cediranib maleate and a placebo once daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Blood and tissue samples are collected from some patients for genetic profiling and biomarker analysis. Peer Reviewed and Funded or Endorsed by Cancer Research UK.
Interventions
DRUGcediranib maleate
DRUGgefitinib
DRUGPlacebo
Sponsors
AstraZeneca
University College, London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed glioblastoma * Measurable disease by MRI * Completed standard first-line treatment for glioblastoma including surgery (unless not received due to anatomical location), radiotherapy and temozolomide (last dose given at least 28 days prior to enrollment) * No other prior treatment for glioblastoma except Gliadel or steroids * Recurrent or progressive disease after standard first-line treatment * No disease progression within 3 months of completion of radiotherapy * No intra- or peri-tumoral hemorrhage PATIENT CHARACTERISTICS: * Karnofsky performance status 70-100% * Mini-mental status score ≥ 15 * Life expectancy ≥ 12 weeks * Serum bilirubin, ALT/AST, creatinine, and urine protein normal * Adequate bone marrow reserve * Not pregnant or nursing * Normal ECG * No history of familial long QT syndrome * No absorption or swallowing difficulties * No uncontrolled hypertension or cardiac ventricular arrhythmias * No current or history of uncontrolled hypertension or requiring maximal doses of calcium channel blockers * No severe or uncontrolled disease * No history of lung disease * No recent hemorrhage or hemoptysis * No known hypersensitivity to cediranib maleate, gefitinib, or any excipients * No history of other malignancies except adequately treated basal cell or squamous cell carcinoma or carcinoma in situ within the past 5 years, unless disease-free for 2 years with tissue diagnosis * No known HIV positivity * No known hepatitis B or C infection * No unhealed surgical incision * Not involved in planning or conducting this study PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from prior anticancer therapy, including radiotherapy * At least 3 months since prior cranial radiation * At least 30 days since prior investigational drugs * At least 28 days since prior craniotomy * At least 2 weeks since prior enzyme-inducing antiepileptic drugs * At least 2 weeks since prior and no concurrent dexamethasone (\> 8 mg/day) or equivalent * At least 14 days since prior major surgery or brain biopsy * No concurrent steroids OR on stable dose 5 days prior to baseline MRI * No other concurrent anticancer therapy, except for steroids (dexamethasone only) * No previous enrollment on the current study * No prior inhibitors of angiogenesis, EGFR, or downstream targets * No prior radiosurgery or brachytherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | from the date of randomisation to the date of first progression or death due to any cause, until 6 months from the date the last patient finished trial treatment (the day after the date that the last trial drug was taken) | Progression free survival (PFS) defined as the time from the date of randomisation to the date of first progression or death due to any cause, whichever one comes first. The progression definition will be based on modified RANO criteria (Wen 2010), such that progression will be defined as the earliest time that at least one of the following occurs: 1. Clinical deterioration 2. Failure to return for evaluation as a result of death or deteriorating condition Or, by retrospective radiographic central review: 3. Any new lesion 4. Increase in ≥25% of sum of the products of perpendicular diameters of enhancing lesions compared with baseline scan, on stable or increasing doses of steroids (dexamethasone) compared to baseline (T1 post-contrast scan) 5. Clear progression of non-measureable disease 6. Significant increase in T2/FLAIR non-enhancing lesion - on stable or increasing steroids (dexamethasone) compared with baseline or best response not caused by co-morbid events. |
Secondary
| Measure | Time frame |
|---|---|
| Radiographic Response Rate | from baseline scan to six week and 12 week scans |
| Progression-free Survival Rate at 6 Months | from the date of randomisation to 6 months |
| Overall Survival | from date of randomization to date of Death due to any cause. |
| Time to Deterioration of Neurological Status | from date of randomization to the date of first neurological status worsening in comparison to baseline (first of 2 confirmatory reports at 2 consecutive visits, 6 weeks apart) as assessed by the clinician, or until date of death, whichever is first. |
| Safety and Tolerability | from date of randomisation to death |
| Steroid Use | from randomization to first increase in dexamethasone dose |
Countries
United Kingdom
Participant flow
Pre-assignment details
Trial closed prematurely because cediranib manufacture was discontinued by AZ. Only 38 patients were recruited
Participants by arm
| Arm | Count |
|---|---|
| Cediranib & Gefitinib Cediranib maleate 30mg od orally and gefitinib 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit.
cediranib maleate
gefitinib | 19 |
| Cediranbib & Placebo Cediranib maleate 30mg od orally and placebo 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit.
cediranib maleate
Placebo | 19 |
| Total | 38 |
Baseline characteristics
| Characteristic | Cediranbib & Placebo | Cediranib & Gefitinib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 15 Participants | 30 Participants |
| Age, Continuous | 56.9 years | 54.4 years | 55.7 years |
| Region of Enrollment United Kingdom | 19 participants | 19 participants | 38 participants |
| Sex: Female, Male Female | 14 Participants | 13 Participants | 27 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 18 | 12 / 19 |
| serious Total, serious adverse events | 5 / 18 | 7 / 19 |
Outcome results
Primary
Progression-free Survival
Progression free survival (PFS) defined as the time from the date of randomisation to the date of first progression or death due to any cause, whichever one comes first. The progression definition will be based on modified RANO criteria (Wen 2010), such that progression will be defined as the earliest time that at least one of the following occurs: 1. Clinical deterioration 2. Failure to return for evaluation as a result of death or deteriorating condition Or, by retrospective radiographic central review: 3. Any new lesion 4. Increase in ≥25% of sum of the products of perpendicular diameters of enhancing lesions compared with baseline scan, on stable or increasing doses of steroids (dexamethasone) compared to baseline (T1 post-contrast scan) 5. Clear progression of non-measureable disease 6. Significant increase in T2/FLAIR non-enhancing lesion - on stable or increasing steroids (dexamethasone) compared with baseline or best response not caused by co-morbid events.
Time frame: from the date of randomisation to the date of first progression or death due to any cause, until 6 months from the date the last patient finished trial treatment (the day after the date that the last trial drug was taken)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cediranib & Gefitinib | Progression-free Survival | 3.6 months |
| Cediranbib & Placebo | Progression-free Survival | 2.8 months |
Secondary
Overall Survival
Time frame: from date of randomization to date of Death due to any cause.
Secondary
Progression-free Survival Rate at 6 Months
Time frame: from the date of randomisation to 6 months
Secondary
Radiographic Response Rate
Time frame: from baseline scan to six week and 12 week scans
Secondary
Safety and Tolerability
Time frame: from date of randomisation to death
Secondary
Steroid Use
Time frame: from randomization to first increase in dexamethasone dose
Secondary
Time to Deterioration of Neurological Status
Time frame: from date of randomization to the date of first neurological status worsening in comparison to baseline (first of 2 confirmatory reports at 2 consecutive visits, 6 weeks apart) as assessed by the clinician, or until date of death, whichever is first.