Phase I/II Study of ZD6474 (Vandetanib) With Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients With Newly-Diagnosed Glioblastoma
Overview
- Phase
- Phase 1
- Intervention
- temozolomide
- Conditions
- Glioblastoma Multiforme
- Sponsor
- Patrick Y. Wen, MD
- Enrollment
- 119
- Locations
- 7
- Primary Endpoint
- Number of Participants That Experienced a Dose-limiting Toxicity (DLT)
- Status
- Completed
- Last Updated
- 7 years ago
Overview
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.
Investigators
Patrick Y. Wen, MD
Director, Center For Neuro-Oncology
Dana-Farber/Brigham and Women's Cancer Center
Eligibility Criteria
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 ZD
- •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).
Exclusion Criteria
- •Subjects must not have had prior cranial radiation therapy.
- •Subjects must not have received prior cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy for brain tumors.
- •Subjects must not have received prior Gliadel wafers.
- •Subjects must not have received any investigational agents within 30 days prior to commencing study treatment
- •Subjects must not have evidence of severe or uncontrolled systemic disease or any concurrent condition that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy.
- •Subjects with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.
- •Subjects must not have any unresolved toxicity greater than CTC grade 1 related to previous anti-cancer therapy.
- •Subjects must not have active infection.
- •Subjects must not be pregnant/breast feeding.
- •Subjects must not have any disease that will obscure toxicity or dangerously alter drug metabolism.
Arms & Interventions
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 \[at 150 mg/m2/day orally for 5 days (days 1-5) of a 28-day TMZ cycle; if 150 mg/m2/day is tolerated without difficulty and the investigator feels the patient can tolerate 200 mg/m2/day, then an increase to a maximum of 200 mg/m2/day for five days every 28 days may be given\].
Intervention: temozolomide
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 \[at 150 mg/m2/day orally for 5 days (days 1-5) of a 28-day TMZ cycle; if 150 mg/m2/day is tolerated without difficulty and the investigator feels the patient can tolerate 200 mg/m2/day, then an increase to a maximum of 200 mg/m2/day for five days every 28 days may be given\].
Intervention: Radiation Therapy
Phase I + Phase II: Arm B (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.
Intervention: ZD6474
Phase I + Phase II: Arm B (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.
Intervention: temozolomide
Phase I + Phase II: Arm B (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.
Intervention: Radiation Therapy
Outcomes
Primary Outcomes
Number of Participants That Experienced a Dose-limiting Toxicity (DLT)
Time Frame: 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
Time Frame: 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 Outcomes
- Median Progression-free Survival (PFS), as Calculated by the # of Months Patients Remain Progression-free(3 years)
- 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.)
- 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.)