Overview

This trial is active, not recruiting.

Conditions glioblastoma multiforme, gliosarcoma
Treatments zd6474, temozolomide, radiation therapy
Phase phase 1/phase 2
Targets VEGF, EGFR
Sponsor Patrick Y. Wen, MD
Collaborator Dana-Farber Cancer Institute
Start date May 2007
End date August 2013
Trial size 119 participants
Trial identifier NCT00441142, 06-377, IRUSZACT0018

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Active Comparator)
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].
temozolomide Temodar
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.
radiation therapy RT
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.
(Experimental)
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.
zd6474 Vandetanib
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
temozolomide Temodar
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.
radiation therapy RT
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.

Primary Outcomes

Measure
Number of Participants That Experienced a Dose-limiting Toxicity (DLT)
time frame: 2 years
Median Overall Survival (OS) of Phase II Patients
time frame: 3 years

Secondary Outcomes

Measure
Median Progression-free Survival (PFS), as Calculated by the # of Months Patients Remain Progression-free
time frame: 3 years
PHASE II: To Further Evaluate the Safety Profile of ZD6474 (Vandetanib) in Combination With Radiation Therapy and Temozolomide in This Patient Population.
time frame: 3 years
PHASE I: To Define the Safety of ZD6474 (Vandetanib) With Radiation Therapy and Concomitant and Adjuvant Temozolomide in This Population.
time frame: 2 years

Eligibility Criteria

Male or female participants at least 18 years old.

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 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 within 3 months before entry; or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia. - No history of arrhythmia (multifocal premature ventricular contractions (PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded. - No previous history of QTc prolongation as a result from other medication that required discontinuation of that medication. - No congenital long QT syndrome, or1st degree relative with unexplained sudden death under 40 years of age. - No left bundle branch block (LBBB). - Subject's screening ECG cannot indicate QTc (with Bazett's correction) that is either unmeasurable or >/= 480 msec on. If subject's screening QTc >/= 480 msec, it may be repeated twice (at least 24 hours apart). The average QTc from the 3 screening ECGs must be < 480 msec. Patients who are receiving a drug that has a risk of inducing Torsades de Pointes are excluded if QTc is >/= 460 msec. - Subjects must not be taking any enzyme-inducing anti-epileptic drugs (EIAED) or other drugs that are potent inducers of CYP3A4 function (rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbitol and St. John's Wort). If patients were previously on EIAEDs and these have been discontinued, patients must have been off the agent for at least 7 days prior to registration. - Subjects must not be taking concomitant medications known to prolong the QT interval and have a risk of inducing Torsade de Pointes (TdP). Any concurrent medication with a known risk of inducing TdP that, in the investigator's opinion cannot be discontinued, will be allowed; however, these patients must be monitored closely. - Subjects must not have uncontrolled hypertension (high blood pressure). - Subjects must not have active diarrhea that may affect the ability of the patient to absorb or tolerate ZD6474 (Vandetanib). - Subjects with confirmed diagnosis of human immunodeficiency virus (HIV) infection are excluded at the investigator's discretion if he/she feels that 1) a potential drug interaction between ZD6474 (Vandetanib) and any of the patient's anti-HIV medications could influence the efficacy of the anti-HIV medication, or 2) it may place the patient at risk due to the pharmacologic activity of ZD6474 (Vandetanib). - Subjects' pre-operative MRI must not demonstrate significant intratumoral or peritumoral hemorrhage & post-operative MRI must not demonstrate a large amount of peri-operative parenchymal hemorrhage. (Patients may have postoperative intracavitary blood.) - Subjects must not have had major surgery (unrelated to the glioblastoma) within 4 weeks before starting study therapy, and subjects cannot have a surgical incision that has not completely healed before starting study therapy. - Subjects must not be receiving Coumadin (subjects may take low molecular weight heparin). - Subjects must not have enrolled on this trial previously. - Subjects must have had no involvement in the planning or conduct of the study (applies to both AstraZeneca staff or staff at the study site). - Any of the following lab results will result in patient exclusion from trial: - Potassium: < 4.0 mmol/L despite supplementation, or above the CTCAE grade 1 upper limit. - Magnesium below the normal range despite supplementation, or above the CTCAE grade 1 upper limit. - Serum calcium above the CTCAE grade 1 upper limit. NOTE: In cases where the serum calcium is below the normal range, 2 options would be available: - The calcium adjusted for albumin is to be obtained and substituted for the measured serum value. Exclusion is to then be based on the adjusted for albumin values falling below the normal limit. - Determine the ionized calcium levels. If these ionized calcium levels are out of normal range despite supplementation, then the patient must be excluded.

Additional Information

Official title Phase I/II Study of ZD6474 (Vandetanib) With Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients With Newly-Diagnosed Glioblastoma
Principal investigator Patrick Y Wen, MD
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.
Trial information was received from ClinicalTrials.gov and was last updated in February 2015.
Information provided to ClinicalTrials.gov by Dana-Farber Cancer Institute.