Glioblastoma Multiforme, Gliosarcoma
Conditions
Keywords
Newly diagnosed malignant brain tumors.
Brief summary
Phase I: The purpose of this research study is to determine the safety of the combination treatment of ZD6474 (Vandetanib) with the standard therapy for glioblastomas and gliosarcomas, temozolomide (Temodar) and radiation therapy. This agent is investigational for the treatment of glioblastomas. We will determine the highest dose of ZD6474 (Vandetanib) that can be given safely when combined with temozolomide (Temodar) and radiation therapy. Phase II: The purpose of this research study is to determine the efficacy of the combination treatment of ZD6474 (Vandetanib) with the standard therapy for glioblastomas and gliosarcomas, temozolomide (Temodar) and radiation therapy. This agent is investigational for the treatment of glioblastomas. All subjects participating in this research study must NOT be taking a certain type of anti-seizure medication called enzyme inducing anticonvulsant drugs. These drugs include (but are not limited to) the following medications: Dilantin, Tegretol, Phenobarbital and trileptal.
Detailed description
Currently the standard treatment for glioblastomas and gliosarcomas is temozolomide (Temodar) and radiation therapy. This study is being done because research has shown that glioblastomas have genetic changes that may cause an excess of certain cell growth factors and their receptors, which can cause uncontrolled tumor growth. The drug being used in this research study, ZD6474 (Vandetanib), is designed to block the receptors to two of these growth factors, the vascular endothelial growth factor (VEGF) and the epidermal growth factor (EGF). These growth factors are important in pathways that promote tumor growth and increasing blood supply to the tumor. Blocking these receptors may reduce the blood supply to the tumor and help slow down tumor growth. There is also laboratory evidence that blocking these receptors may increase the sensitivity of glioblastomas to radiation therapy. This research study is a Phase I/II clinical trial. Phase I clinical trials test the safety of an investigational drug. Phase I studies also try to define the appropriate dose of the investigational drug to use for further studies. We will determine the highest dose of ZD6474 (Vandetanib) that can be given safely when combined with temozolomide (Temodar) and radiation therapy. The purpose of Phase II of this research study is to determine the efficacy of the combination treatment of ZD6474 (Vandetanib) with the standard therapy for glioblastomas and gliosarcomas, temozolomide (Temodar) and radiation therapy. It will look to see how patients fare on treatment (if they progress and when, how they are doing after 12 months of treatment). In this research study, the safety of the combination treatment of ZD6474 (Vandetanib) with the standard therapy for glioblastomas and gliosarcomas, temozolomide (Temodar) and radiation therapy will be further evaluated. We will also be looking at samples to see if there are correlations between them and how well patients do on treatment. This agent is investigational for the treatment of glioblastomas. Investigational means that the drug is still being studied and that research doctors are trying to find out more about it. It also means that the FDA (U.S. Food and Drug Administration) has not approved ZD6474 (Vandetanib) for use for your type of cancer. All subjects participating in this research study must NOT be taking a certain type of anti-seizure medication called enzyme inducing anticonvulsant drugs. These drugs include the following medications: Dilantin, Tegretol, Phenobarbital and trileptal.
Interventions
DRUGZD6474
Taken orally once a day (at 100 mg/day is the phase II dose; the MTD determined by the phase I portion of the trial) until disease gets worse or participants experience unacceptable side effects
DRUGtemozolomide
During the 'Induction' phase: 75/mg/m2/day temozolomide will be given orally daily for 6 weeks (42 days) during radiation therapy, beginning either the night before or on the first day of the first fraction of radiation, including weekends and holidays. This is followed by a 4-6 week break. During the 'Maintenance' phase: The first post-radiation temozolomide cycle will be administered at 150 mg/m2/day orally for 5 days (days 1-5) of a 28-day TMZ cycle. If 150 mg/m2/day is tolerated without difficulty and the investigator feels the patient can tolerate 200 mg/m2/day, then an increase to a maximum of 200 mg/m2/day for five days every 28 days may be given. This is given for 12 cycles.
RADIATIONRadiation Therapy
Radiotherapy must be given by external beam to a partial brain field in daily fractions of 180-200 cGy, to a planned total dose to the tumor of approximately 6000 cGy.
Sponsors
Dana-Farber Cancer Institute
Beth Israel Deaconess Medical Center
Massachusetts General Hospital
University of Virginia
Memorial Sloan Kettering Cancer Center
Henry Ford Hospital
Patrick Y. Wen, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All inclusion and
Exclusion criteria
apply to both phase I and II patients. Inclusion Criteria: * Subjects with histologically proven intracranial glioblastoma multiforme (GBM) and gliosarcoma will be eligible for this protocol. * Gadolinium MRI or contrast CT must be obtained within 14 days prior to registration. * Patients must have a plan to begin treatment with ZD6474 (vandetanib) and/or temozolomide 21 to 35 days after surgical resection or 14 to 35 days after stereotactic biopsy. * Subjects must have a plan to begin partial brain radiotherapy 5-7 days after beginning ZD6474. Radiotherapy must be a) at the Radiation Oncology Department of the participating institution, b) at an affiliated site that is currently approved to participate in any trial of the Radiation Therapy Oncology Group (RTOG), or c) at another location with prior approval from the Overall PI of the trial. Radiotherapy must be given by external beam to a partial brain field in daily fractions of 180 to 200 cGy, to a planned total dose to the tumor of approximately 6000 cGy. Stereotactic radiosurgery and brachytherapy will not be allowed. * If it is deemed in the best interest of the patient, intensity modulated radiation therapy (IMRT) is allowable on this trial. If IMRT is administered, dose specifics must be conducted per institutional guidelines. * Subjects must be willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while being treated with ZD6474 (ZactimaTM), with the exception of temozolomide. * All subjects must sign an informed consent indicating that they are aware of the investigational nature of this study prior to any study-related procedures. Patients must be registered with in the Dana Farber Cancer Institute's Quality Assurance Office for Clinical Trials prior to treatment with ZD6474 (Vandetanib). Patients must sign an authorization for the release of their protected health information. * Subjects can be male or female, and must be \>/= 18 years old, with a life expectancy \> 12 weeks. * Subjects must be able to care for themselves (KPS\>/=60). * Subjects must have adequate labs as defined below: * Patients must have adequate bone marrow function (WBC \>/= 3,000/μl, ANC \>/= 1,500/mm3, platelet count of \>/= 100,000/mm3, and hemoglobin \>/= 10 gm/dl), adequate liver function (SGOT, SGPT \</= 2.5 times ULN; bilirubin \</= 1.5 times ULN), and adequate renal function (creatinine \< 1.5 mg/dL, and/or serum creatinine \</= 1.5 x ULN, and/or creatinine clearance \> 30 mL/min, calculated by Cockcroft-Gault formula) before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion. * Patients must have potassium \>/= 4.0 mmol/L and serum calcium (ionized or adjusted for albumin) or magnesium in the normal range (supplementation is allowed). * Patients' alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be \</= 2.5 X ULRR and their alkaline phosphatase (ALP) \</= 2.5 x ULRR, (or \</= 5x ULRR if judged by the investigator to be related to liver metastases) * Women of childbearing potential must have a negative pregnancy test documented within 14 days prior to registration. * Men and women of childbearing potential must agree to use adequate contraception while receiving study medication and continue for at least two months (five half-lives) after their last dose of study medication. * Patients must have sufficient tissue available from their prior biopsy/surgery: at least 10 (preferably 20) unstained slides or 1 tissue block. * Patients must agree not to donate blood during the trial and for 3 months following their last dose of trial treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Experienced a Dose-limiting Toxicity (DLT) | 2 years | The primary outcome of Phase I of this trial was to determine the maximum tolerated dose (MTD) of ZD6474 (Vandetanib) in patients with newly-diagnosed glioblastomas multiforme (GBM) and gliosarcomas who are also receiving radiation therapy with concomitant and adjuvant temozolomide. The MTD is the dose level at which 0/6 or 1/6 patients experience a dose-limiting toxicity (DLT) with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. |
| Median Overall Survival (OS) of Phase II Patients | 3 years | The primary outcome of Phase II of this trial was to determine the efficacy of ZD6474 (Vandetanib) in combination with radiation therapy and concomitant and adjuvant temozolomide in patients with newly-diagnosed GBM and gliosarcomas as measured by overall survival and median survival. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free Survival (PFS), as Calculated by the # of Months Patients Remain Progression-free | 3 years | A secondary outcome of Phase II of this trial is the median progression-free survival (PFS), as calculated by the # of months patients remain progression-free |
| PHASE II: Percentage of Grade 3-5 Treatment-Related Adverse Events | Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study treatment until 30 days after the last dose of study treatment), maximum timeframe was 6 years. | The percentage of adverse events (based on CTCAEv3) reported on study (via case report forms and Reportable AE submissions) that are both high-grade (grade 3, 4, or 5) and considered at least possibly related to study treatment. |
| PHASE I: Percentage of Grade 3-5 Treatment-Related Adverse Events | Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study treatment until 30 days after the last dose of study treatment), maximum timeframe was 7 years. | The percentage of adverse events (based on CTCAEv3) reported on study (via case report forms and Reportable AE submissions) that are both high-grade (grade 3, 4, or 5) and considered at least possibly related to study treatment. |
Countries
United States
Participant flow
Pre-assignment details
Although 119 pts were registered & enrolled to trial, only 111 began study tx (8 enrolled pts did not receive tx on study). 7 pts randomized to Ph II Arm A removed their consent before starting study tx, and 1 Ph II Arm B pt was removed from study before starting tx, as pt clinically declined immediately following registration/randomization.
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Dose Level -1: RT + TMZ + Vandetanib @ 200 mg/Day ZD6474 (Vandetanib) daily (to begin 5-7 days prior to starting participant's RT) Temozolomide (75 mg/m2 daily for 6 weeks) with concurrent fractionated radiation therapy for approximately 6 weeks (XRT must be given by external beam to a partial brain field in daily fractions of 180-200 cGy, to a planned total dose to the tumor of approximately 6000 cGy), followed by 4-6 weeks rest.
Followed by:
12 cycles of adjuvant temozolomide \[at 150 mg/m2/day orally for 5 days (days 1-5) of a 28-day TMZ cycle; if 150 mg/m2/day is tolerated without difficulty and the investigator feels the patient can tolerate 200 mg/m2/day, then an increase to a maximum of 200 mg/m2/day for five days every 28 days may be given\].
ZD6474 (Vandetanib) daily for the twelve (12) 28-day cycles of adjuvant temozolomide, with the option to continue until participant experiences an unacceptable toxicity or his/her tumor progresses. | 6 |
| Phase I: Dose Level -2: RT + TMZ + Vandetanib @ 100 mg/Day ZD6474 (Vandetanib) daily (to begin 5-7 days prior to starting participant's RT) Temozolomide (75 mg/m2 daily for 6 weeks) with concurrent fractionated radiation therapy for approximately 6 weeks (XRT must be given by external beam to a partial brain field in daily fractions of 180-200 cGy, to a planned total dose to the tumor of approximately 6000 cGy), followed by 4-6 weeks rest.
Followed by:
12 cycles of adjuvant temozolomide \[at 150 mg/m2/day orally for 5 days (days 1-5) of a 28-day TMZ cycle; if 150 mg/m2/day is tolerated without difficulty and the investigator feels the patient can tolerate 200 mg/m2/day, then an increase to a maximum of 200 mg/m2/day for five days every 28 days may be given\].
ZD6474 (Vandetanib) daily for the twelve (12) 28-day cycles of adjuvant temozolomide, with the option to continue until participant experiences an unacceptable toxicity or his/her tumor progresses. | 7 |
| Phase II: Arm A (Control Group: RT + TMZ) The Induction Phase:
Temozolomide (75 mg/m2 daily for 6 weeks) with concurrent fractionated radiation therapy for approximately 6 weeks (XRT must be given by external beam to a partial brain field in daily fractions of 180-200 cGy, to a planned total dose to the tumor of approximately 6000 cGy), followed by 4-6 weeks rest.
Followed by the Maintenance Phase:
12 cycles of adjuvant temozolomide \[at 150 mg/m2/day orally for 5 days (days 1-5) of a 28-day TMZ cycle; if 150 mg/m2/day is tolerated without difficulty and the investigator feels the patient can tolerate 200 mg/m2/day, then an increase to a maximum of 200 mg/m2/day for five days every 28 days may be given\]. | 29 |
| Phase II: Arm B (Experimental Group: RT + TMZ + Vandetanib) The Induction Phase:
ZD6474 (Vandetanib) daily (to begin 5-7 days prior to starting participant's RT) Temozolomide (75 mg/m2 daily for 6 weeks) with concurrent fractionated radiation therapy for approximately 6 weeks (XRT must be given by external beam to a partial brain field in daily fractions of 180-200 cGy, to a planned total dose to the tumor of approximately 6000 cGy), followed by 4-6 weeks rest.
Followed by the Maintenance Phase:
12 cycles of adjuvant temozolomide \[at 150 mg/m2/day orally for 5 days (days 1-5) of a 28-day TMZ cycle; if 150 mg/m2/day is tolerated without difficulty and the investigator feels the patient can tolerate 200 mg/m2/day, then an increase to a maximum of 200 mg/m2/day for five days every 28 days may be given\].
ZD6474 (Vandetanib) daily for the twelve (12) 28-day cycles of adjuvant temozolomide, with the option to continue until participant experiences an unacceptable toxicity or his/her tumor progresses. | 69 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 | 3 | 22 |
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 3 | 3 | 17 | 32 |
| Overall Study | Patient still receiving active study tx | 1 | 0 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 10 |
Baseline characteristics
| Characteristic | Phase I: Dose Level -1: RT + TMZ + Vandetanib @ 200 mg/Day | Phase I: Dose Level -2: RT + TMZ + Vandetanib @ 100 mg/Day | Phase II: Arm A (Control Group: RT + TMZ) | Phase II: Arm B (Experimental Group: RT + TMZ + Vandetanib) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 5 Participants | 19 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 5 Participants | 24 Participants | 50 Participants | 85 Participants |
| Baseline (Day 1) Karnofsky Performance Score (KPS) 100 | 0 Participants | 5 Participants | 7 Participants | 15 Participants | 27 Participants |
| Baseline (Day 1) Karnofsky Performance Score (KPS) 60 | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Baseline (Day 1) Karnofsky Performance Score (KPS) 70 | 3 Participants | 0 Participants | 3 Participants | 5 Participants | 11 Participants |
| Baseline (Day 1) Karnofsky Performance Score (KPS) 80 | 1 Participants | 0 Participants | 2 Participants | 17 Participants | 20 Participants |
| Baseline (Day 1) Karnofsky Performance Score (KPS) 90 | 2 Participants | 2 Participants | 15 Participants | 30 Participants | 49 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) White | 6 Participants | 7 Participants | 25 Participants | 63 Participants | 101 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 13 Participants | 25 Participants | 41 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 16 Participants | 44 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 81 / 82 | 28 / 29 |
| serious Total, serious adverse events | 52 / 82 | 15 / 30 |
Outcome results
Primary
Median Overall Survival (OS) of Phase II Patients
The primary outcome of Phase II of this trial was to determine the efficacy of ZD6474 (Vandetanib) in combination with radiation therapy and concomitant and adjuvant temozolomide in patients with newly-diagnosed GBM and gliosarcomas as measured by overall survival and median survival.
Time frame: 3 years
Population: This measure was only assessed in Participants in Phase II part of the study, who had available data for analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: Arm A (Control Group: RT + TMZ) | Median Overall Survival (OS) of Phase II Patients | 15.9 months |
| Phase II: Arm B (Experimental Group: RT + TMZ + Vandetanib) | Median Overall Survival (OS) of Phase II Patients | 16.6 months |
Primary
Number of Participants That Experienced a Dose-limiting Toxicity (DLT)
The primary outcome of Phase I of this trial was to determine the maximum tolerated dose (MTD) of ZD6474 (Vandetanib) in patients with newly-diagnosed glioblastomas multiforme (GBM) and gliosarcomas who are also receiving radiation therapy with concomitant and adjuvant temozolomide. The MTD is the dose level at which 0/6 or 1/6 patients experience a dose-limiting toxicity (DLT) with the next higher dose having at least 2/3 or 2/6 patients encountering DLT.
Time frame: 2 years
Population: This measure was only assessed in Participants enrolled into the Phase I part of the study who had available data for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dose Level -1: RT + TMZ + Vandetanib @ 200 mg/Day | Number of Participants That Experienced a Dose-limiting Toxicity (DLT) | 3 Participants |
| Phase I: Dose Level -2: RT + TMZ + Vandetanib @ 100 mg/Day | Number of Participants That Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
Secondary
Median Progression-free Survival (PFS), as Calculated by the # of Months Patients Remain Progression-free
A secondary outcome of Phase II of this trial is the median progression-free survival (PFS), as calculated by the # of months patients remain progression-free
Time frame: 3 years
Population: This is an outcome for Phase II participants only; 0 Phase I participants were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: Arm A (Control Group: RT + TMZ) | Median Progression-free Survival (PFS), as Calculated by the # of Months Patients Remain Progression-free | 6.2 months |
| Phase II: Arm B (Experimental Group: RT + TMZ + Vandetanib) | Median Progression-free Survival (PFS), as Calculated by the # of Months Patients Remain Progression-free | 7.7 months |
Secondary
PHASE II: Percentage of Grade 3-5 Treatment-Related Adverse Events
The percentage of adverse events (based on CTCAEv3) reported on study (via case report forms and Reportable AE submissions) that are both high-grade (grade 3, 4, or 5) and considered at least possibly related to study treatment.
Time frame: Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study treatment until 30 days after the last dose of study treatment), maximum timeframe was 6 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dose Level -1: RT + TMZ + Vandetanib @ 200 mg/Day | PHASE II: Percentage of Grade 3-5 Treatment-Related Adverse Events | 4.16 percentage of events |
| Phase I: Dose Level -2: RT + TMZ + Vandetanib @ 100 mg/Day | PHASE II: Percentage of Grade 3-5 Treatment-Related Adverse Events | 8.37 percentage of events |
Secondary
PHASE I: Percentage of Grade 3-5 Treatment-Related Adverse Events
The percentage of adverse events (based on CTCAEv3) reported on study (via case report forms and Reportable AE submissions) that are both high-grade (grade 3, 4, or 5) and considered at least possibly related to study treatment.
Time frame: Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study treatment until 30 days after the last dose of study treatment), maximum timeframe was 7 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dose Level -1: RT + TMZ + Vandetanib @ 200 mg/Day | PHASE I: Percentage of Grade 3-5 Treatment-Related Adverse Events | 9.48 percentage of events |
| Phase I: Dose Level -2: RT + TMZ + Vandetanib @ 100 mg/Day | PHASE I: Percentage of Grade 3-5 Treatment-Related Adverse Events | 4.43 percentage of events |