Official Title: “Phase I/II Study of ZD6474 (Vandetanib) With Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients With Newly-Diagnosed Glioblastoma”

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 the following medications: Dilantin, Tegretol, Phenobarbital and trileptal.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Parallel Assignment, Efficacy Study

Study Primary Completion Date: May 2010

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 are do 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.

Intervention(s) in this Clinical Trial

• Drug: ZD6474
  • 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
• Drug: temozolomide
  • 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: Radiation 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.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: A
  • The "Induction" Phase of treatment consists of 6 weeks of radiation therapy (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) with concomitant temozolomide [75/mg/m2/day orally daily for 6 weeks (42 days) during radiation therapy] plus a 4-6 week break, and is followed by the "Maintenance" Phase of therapy, which consists of treatment with 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]. For those patients on Arm A of the Phase II portion of the study, post-radiation temozolomide treatment should begin as close to the beginning of week 11 as possible.
• Experimental: B
  • Arm B patients will be treated with ZD6474 orally at 100 mg/day throughout study treatment. The "Induction" Phase of treatment consists of 6 weeks of radiation therapy with concomitant temozolomide plus a 4-6 week break, and is followed by the "Maintenance" Phase of therapy, which consists of treatment with 12 cycles of adjuvant temozolomide. In patients who will receive both ZD6474 (vandetanib) and temozolomide, ideally, the start of post-radiation temozolomide treatment will coincide with the initiation of the next planned 28-day "cycle" of ZD6474 (Vandetanib), ideally at the start of week 13. After the course of adjuvant temozolomide is completed, treatment with ZD6474 (Vandetanib) alone will continue indefinitely as long as there are no unacceptable toxicities and no tumor progression.

Primary Measures

• PHASE I: To determine the maximum tolerated dose of ZD6474 (Vandetanib) in patients with newly-diagnosed glioblastomas multiforme (GBM) and gliosarcomas who are also receiving radiation therapy with concomitant and adjuvant temozolomide.
  • Time Frame: 2 years
    Safety Issue?: Yes
• PHASE II: 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
    Safety Issue?: No

Secondary Measures

• PHASE II: To determine the 12-month survival and median time to tumor progression.
  • Time Frame: 3 years
    Safety Issue?: No
• 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
    Safety Issue?: Yes
• PHASE I: To define the safety of ZD6474 (Vandetanib) with radiation therapy and concomitant and adjuvant temozolomide in this population.
  • Time Frame: 2 years
    Safety Issue?: Yes

• 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.
• Diagnosis will have been established by biopsy or resection no more than 4 weeks (28 days) prior to registration.
• Gadolinium MRI or contrast CT must be obtained within 14 days prior to registration.
• Subjects must have a plan to begin treatment with ZD6474 (vandetanib) and/or temozolomide no sooner than 3 weeks (21 days) after surgical resection or 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, or b) at an affiliated site that is currently approved to participate in any trial of the Radiation Therapy Oncology Group (RTOG).
• 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.
• Subjects must be > 18 years old.
• Subjects must be able to care for themselves.
• 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.

Exclusion Criteria:

• Subjects must not have had prior cranial radiation therapy.
• Subjects must not have had prior treatment for brain tumors.
• Subjects must not have received prior Gliadel wafers.
• Subjects must not have any significant medical illnesses.
• 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 history of any clinically significant cardiac event, or evidence of heart disease.
• Subjects must not have any enzyme-inducing anti-epileptic drugs (Dilantin, Tegretol, valproic acid, trileptal.
• Subjects must not have uncontrolled high blood pressure.
• Subjects must not have active diarrhea that may affect the ability of the patient to absorb or tolerate ZD6474 (ZactimaTM).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Dana-Farber Cancer Institute

Overall Clinical Trial Officials and Contacts

Patrick Y Wen, MD Principal Investigator Dana-Farber Cancer Institute  

Overall Contact: Patrick Y Wen, MD 617-632-2166 pwen@partners.org

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00441142

Study ID Number: 06-377

ClinicalTrials.gov Identifier: NCT00441142

Health Authority: United States: Food and Drug Administration