Glioblastoma, Gliosarcoma
Conditions
Keywords
recurrent glioblastoma, temodar, temozolomide
Brief summary
Temozolomide (Temodar) is an FDA approved medication for the treatment of newly diagnosed glioblastomas. In this study, we will be using temozolomide to treat recurrent glioblastomas. We will be using a different dose and schedule than the FDA approved dose and schedule. The purpose of this study is to determine if patients that have failed standard temozolomide treatment will respond to temozolomide when given at a different dose and schedule (21 days every 28 days).
Detailed description
* Participants will be given a medication-dosing calendar for each treatment cycle. Each treatment cycle lasts 4 weeks (28 days) during which time they will be taking temozolomide orally once a day for the first three weeks. * At the end of each cycle (day 28, +/- 2 days), the following procedures will be performed: Complete physical examination including a neurological exam; vital signs; a review of current medications and symptoms; blood samples; a pregnancy test for women of child-bearing potential; self-administered quality of life questionnaire; brain MRI or CT scan. * Participants may continue taking temozolomide until their tumor grows or if they experience unacceptable side effects.
Interventions
DRUGTemozolomide
Taken orally daily for the first three weeks of a four-week cycle.
Sponsors
Brigham and Women's Hospital
Massachusetts General Hospital
University of Pennsylvania
Wake Forest University Health Sciences
Tufts Medical Center
Dartmouth-Hitchcock Medical Center
Schering-Plough
Patrick Y. Wen, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must provide independent consent or must demonstrate willingness to participate in the study and to adhere to dose and visit schedules. * 18 years of age or older (of either sex, and of any race) * Histologic diagnosis of GBM or gliosarcoma with an unequivocal progression by MRI or CT scan * Must have received standard combined modality therapy as first-line treatment consisting of RT plus concomitant temozolomide followed by adjuvant temozolomide (at least 2 cycles of adjuvant temozolomide) * Gadolinium MRI or contrast CT scan must be obtained within 14 days prior to registration, and must be on a steroid dose that has been stable for at least 5 days. * Karnofsky Performance status of 60 or greater * Life expectancy of at least 8 weeks * Recovered from the toxic effects of prior therapy, and 21 days must have elapsed since prior treatment with temozolomide o If a patient has residual toxicity from any previous treatment, toxicity must be ≤ Grade 1 * Laboratory tests within parameters outlined in the protocol * Female subjects of childbearing potential & male subjects with female partner of childbearing potential must agree to use a medically accepted method of contraception or be surgically sterilized prior to Screening, while receiving protocol-specified medication, and for 30 days after stopping the study medication * Negative pregnancy test within 48 hours prior to dosing with the study drug (for female subjects of childbearing potential) * Free of any clinically relevant disease that would, in the Principal Investigator's opinion, interfere with the conduct of the study or study evaluations * Must be able to adhere to the dosing and visit schedules, and agree to record medication times, concomitant medications, and adverse events (AEs) accurately and consistently in a daily diary * Unstained slides (at least 15 of 10 micron thickness, or 20 when \< 10 micron thickness)or 1 tissue block must be available from the original diagnostic biopsy/surgery or from the biopsy/surgery recurrence * Participants who have undergone recent resection of recurrent or progressive tumor will be eligible provided at least 2 weeks has elapsed since surgery, and subjects have recovered from surgical-related trauma * Residual disease following resection of recurrent GBM or gliosarcoma is not mandated for eligibility into the study.
Exclusion criteria
* Participant has received a dosing schedule of temozolomide other than 75 mg/m2/day for 42 days during RT followed by adjuvant temozolomide at a dose of 150-200 mg/m2/day for 5 days of a 28-day schedule (standard dose adjustments for toxicity are allowed) * Any other anti-tumor agent other than standard surgical resection, RT and temozolomide prior to enrollment or during the study period * Received treatment with BCNU (Gliadel) wafers or GliaSite * Progressed prior to receiving at least 2 cycles of adjuvant temozolomide * Pregnant or intending to become pregnant during the study * In a situation or condition that, in the opinion of the Investigator, may interfere with optimal participation in the study * Participating in any other clinical study in which an investigational drug is prescribed * Allergic to or has sensitivity to the study drug or its excipients * History of any other cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix), unless he/she is in complete remission and has not received treatment for that particular disease for the past 3 or more years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Month Progression Free Survival | 6 months | Progression is defined using Modified Macdonald Criteria , using a \>/= 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From patient registration until end of study, assessed up to 54 months | — |
| Radiographic Response | From patient registration until end of study, assessed up to 54 months | Responders on study are those with a best response of either CR or PR. Per Modified Macdonald Criteria for lesions assessed by MRI/CT: Complete Response (CR) = Complete disappearance of all measurable and evaluable disease, no new lesions, no evidence of non-evaluable disease, with no steroids. Partial Response (PR) \>/= 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions, no progression of evaluable disease, no new lesions, with steroid dose @ time of response \</= max dose w/in the first 8 weeks of therapy. |
| Time to Progression. | From patient registration until end of study, assessed up to 54 months | Progression is defined using Modified Macdonald Criteria , using a \>/= 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). |
Countries
United States
Participant flow
Recruitment details
Study activated at DFCI in May 2008 and was eventually activated at MGH, UPENN, Wake Forest University Baptist Medical Center, Dartmouth-Hitchcock Medical Center, and Tufts NEMC.
Participants by arm
| Arm | Count |
|---|---|
| 12 Cycles of Dose-Dense Temozolomide (Single Arm Study) Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets) | 58 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Progressive disease | 45 |
Baseline characteristics
| Characteristic | 12 Cycles of Dose-Dense Temozolomide (Single Arm Study) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants |
| Age, Continuous | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 54 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Karnofsky performance status (KPS) at registration | 90 % |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 51 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 58 / 58 |
| serious Total, serious adverse events | 19 / 58 |
Outcome results
Primary
6 Month Progression Free Survival
Progression is defined using Modified Macdonald Criteria , using a \>/= 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time frame: 6 months
Population: Patients evaluable for imaging analysis, as protocol-defined.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 12 Cycles of Dose-Dense Temozolomide (Single Arm Study) | 6 Month Progression Free Survival | 11 percentage of evaluable participants |
Secondary
Overall Survival
Time frame: From patient registration until end of study, assessed up to 54 months
Population: Entire study population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 12 Cycles of Dose-Dense Temozolomide (Single Arm Study) | Overall Survival | 11.7 months |
Secondary
Radiographic Response
Responders on study are those with a best response of either CR or PR. Per Modified Macdonald Criteria for lesions assessed by MRI/CT: Complete Response (CR) = Complete disappearance of all measurable and evaluable disease, no new lesions, no evidence of non-evaluable disease, with no steroids. Partial Response (PR) \>/= 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions, no progression of evaluable disease, no new lesions, with steroid dose @ time of response \</= max dose w/in the first 8 weeks of therapy.
Time frame: From patient registration until end of study, assessed up to 54 months
Population: Of the 58 patients registered, 3 of were ineligible for analysis based on path review, which is why only 55 patients were evaluated for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 12 Cycles of Dose-Dense Temozolomide (Single Arm Study) | Radiographic Response | 13 percentage of participants evaluated |
| Complete Response | Radiographic Response | 0 percentage of participants evaluated |
Secondary
Time to Progression.
Progression is defined using Modified Macdonald Criteria , using a \>/= 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time frame: From patient registration until end of study, assessed up to 54 months
Population: Of the 58 patients registered, 3 of were ineligible for analysis based on path review, which is why only 55 patients were evaluated for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 12 Cycles of Dose-Dense Temozolomide (Single Arm Study) | Time to Progression. | 56 days |