Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioblastoma

Glioma

Astrocytoma

Oligodendroglioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Oligoastrocytoma

Neuroepithelioma

Anticonvulsants

All Drugs and Chemicals

Valproic: 10mg TID week 1, 25mg TID week 2, 35mg week 3

Non-enzyme-inducing anti-epileptic drugs: 25mg TID week 1, 35mg week 2, 50mg week 3

Enzyme-inducing anti-epileptic drugs: 35mg TID week 1, 505mg week 2, 75mg week 3

10mg, 25 mg, 35 mg, 50 mg, 75mg TID for 3 weeks

Talampanel

To analyze the effect of Talampanel on progression free survival in patients with recurrent high grade gliomas.

To determine the efficacy of Talampanel in patients with recurrent malignant glioma as measured by 6-month progression survival, as well as to obtain preliminary information regarding the spectrum of toxicities of the drug among this patient population.

Phase 2 Trial Using Talampanel in Patients With Recurrent High Grade Gliomas

A Phase II Trial of Talampanel in Patients With Recurrent High-Grade Gliomas.

National Cancer Institute (NCI)

Teva Branded Pharmaceutical Products R&D, Inc.

Rivka Kreitman, Ph.D., Vice President, Innovative Research and Development

Nervous System Diseases

Brain Neoplasms

Disease Progression

Gliosarcoma

Antineoplastic Agents

Carboplatin

Sequential Group (carboplatin followed by vandetanib)

Vandetanib is an oral medication known to block angiogenesis and has shown significant antitumor activity in laboratory and animal studies. Vandetanib appears to be well tolerated by patients at specific daily doses.

ZD6474 (Vandetanib)

Carboplatin is a drug that interrupts division of cancer cells and has been shown to be a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating brain tumors, but researchers are interested in gathering more information about how it works as a treatment for patients who have not responded to initial surgery, radiation, or chemotherapy.

Katherine E Warren, M.D.

Background:

* Growth of new blood vessels (angiogenesis) provides many tumors, including brain tumors, with needed nutrients and oxygen for cancer cells to survive. One possible treatment for different kinds of cancer involves treatment with drugs that slow or stop angiogenesis and prevent further tumor growth.
* Vandetanib is an oral medication known to block angiogenesis and has shown significant antitumor activity in laboratory and animal studies. Vandetanib appears to be well tolerated by patients at specific daily doses.
* Carboplatin is a drug that interrupts division of cancer cells and has been shown to be a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating brain tumors, but researchers are interested in gathering more information about how it works as a treatment for patients who have not responded to initial surgery, radiation, or chemotherapy.

Objective:

- To determine the safety and effectiveness of vandetanib and carboplatin, given together or sequentially, against recurrent high-grade gliomas.

Eligibility:

- Adults diagnosed with a malignant glioma who have received standard treatments that no longer appear to be effective.

Design:

* Patients will be assigned to one of two groups. Group 1 patients (combination group) will receive oral vandetanib for 28 days and intravenous (IV) carboplatin (once at the beginning of the 28-day cycle). Group 2 patients (sequential group) will receive IV carboplatin alone (once at the beginning of the 28-day cycle) and then oral vandetanib (300 mg daily) for 28 days if the tumor grows or the patient develops unacceptable carboplatin toxicity.
* Treatment will continue in 28-day cycles for 1 year for both groups.
* Patients will undergo a number of tests and procedures during the treatment cycle, including physical examinations, routine laboratory tests, electrocardiograms, and magnetic resonance imaging (MRI) scans
* At the end of 1 year of treatment, patients will be reevaluated for possible continuation of drug therapy.

Background:

In vivo experiments have documented the ability of vandetanib (ZD6474) to inhibit tumor growth in various preclinical tumor models. Given the pronounced neovasculature associated with malignant gliomas, and abundant published data demonstrating the dependence of glioma growth on the maintenance and proliferation of this neovasculature, vandetanib represents a potentially promising new therapeutic approach to these otherwise refractory tumors. Phase II data of vandetanib for recurrent glioblastomas conducted at the National Institutes of Health showed promising activity but responses were usually short-lasting.

Carboplatin has shown activity as monotherapy in the treatment of recurrent malignant gliomas in adults and preclinical data generated at Dr. Fines' laboratory demonstrate additive anti-glioma activity with vandetanib. The safety profile of carboplatin and the preclinical and clinical data supports its use in combination with vandetanib in patients with malignant gliomas.

Vandetanib is also an epidermal growth factor receptor (EGFR) inhibitor and it has been demonstrated that the presence of the EGFRvIII mutant and/or the presence of an intact phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and non-phosphorylated protein kinase B (AKT) predict for a higher likelihood of response to the EGFR inhibitors Tarceva and Iressa.

Objectives:

To establish data regarding the anti-tumor activity of vandetanib in combination with carboplatin and single agent carboplatin and to collect information regarding the spectrum of toxicities.

To determine if the presence of the EGFRvIII mutant and/or the presence of an intact PTEN and non-phosphorylated AKT predict for a higher likelihood of response to vandetanib.

Eligibility:

Patients with histologically proven malignant glioma are eligible for this study.

Design:

Patients will be randomized (1:1) to one of two groups. Patients in group one will be treated with vandetanib (300 mg daily for patients not on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg daily for patients on EIAEDs) and with carboplatin (area under the concentration-time curve at steady-state \[area under curve (AUC)\], 6mg/mL x min) once every 4-week cycle (combination group). Patients in group two will receive carboplatin alone (AUC 6mg/mL x min) once every 4-week cycle. Patients who develop tumor progression or unacceptable toxicity on carboplatin alone (group 2) can then receive single agent vandetanib (300 mg daily for patients not on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg daily for patients on EIAEDs) in 4-week cycles (sequential group). A total of 128 evaluable patients will be analyzed. The total accrual ceiling will allow for 74 patients to be enrolled in the glioblastoma multiforme (GBM) stratum and 74 patients in the anaplastic gliomas (AG) stratum (total 148) to factor in replacing those patients who come off treatment prior to cycle 1.

A Randomized Phase II Trial of Vandetanib (ZD6474) in Combination With Carboplatin Versus Carboplatin Alone Followed by Vandetanib Alone in Adults With Recurrent High-Grade Gliomas

Percentage of participants who are alive and progression-free at 6 months.

Time between the first day of treatment and the day of death.

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Principal Investigator

Carboplatin: Carboplatin is a drug that interrupts division of cancer cells and has been shown to be a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating brain tumors, but researchers are interested in gathering more information about how it works as a treatment for patients who have not responded to initial surgery, radiation, or chemotherapy.

ZD6474 (Vandetanib): Vandetanib is an oral medication known to block angiogenesis and has shown significant antitumor activity in laboratory and animal studies. Vandetanib appears to be well tolerated by patients at specific daily doses.

Carboplatin: Carboplatin is a drug that interrupts division of cancer cells and has been shown to be a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating brain tumors, but researchers are interested in gathering more information about how it works as a treatment for patients who have not responded to initial surgery, radiation, or chemotherapy.

Vandetanib With Carboplatin

ZD6474 (Vandetanib): Vandetanib is an oral medication known to block angiogenesis and has shown significant antitumor activity in laboratory and animal studies. Vandetanib appears to be well tolerated by patients at specific daily doses.

Crossover to Vandetanib

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Katherine E. Warren

Glioblastoma (Combination)

Glioblastoma (Carboplatin Alone)

Anaplastic Astrocytomas (Combination)

Anaplastic Astrocytomas (Carboplatin Alone)

The group data is displayed per the report provided to the Food and Drug Administration.

Progression Free Survival at 6 Months

Glioblastoma (Carboplation Alone)

Anaplastic Astrocytoma (Combination)

Anaplastic Astrocytoma (Carboplatin Alone)

Overall Survival

Combo Group (both drugs together)

ZD6474 (Vandetanib): Vandetanib is an oral medication known to block angiogenesis and has shown significant antitumor activity in laboratory and animal studies. Vandetanib appears to be well tolerated by patients at specific daily doses.

Carboplatin: Carboplatin is a drug that interrupts division of cancer cells and has been shown to be a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating brain tumors, but researchers are interested in gathering more information about how it works as a treatment for patients who have not responded to initial surgery, radiation, or chemotherapy.

Sequential Group (carboplatin followed by vandetanib)

ZD6474 (Vandetanib): Vandetanib is an oral medication known to block angiogenesis and has shown significant antitumor activity in laboratory and animal studies. Vandetanib appears to be well tolerated by patients at specific daily doses.

Carboplatin: Carboplatin is a drug that interrupts division of cancer cells and has been shown to be a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating brain tumors, but researchers are interested in gathering more information about how it works as a treatment for patients who have not responded to initial surgery, radiation, or chemotherapy.

Cross Over to Vandetanib

Number of Participants With Adverse Events

Overall Study

Bevacizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

GBM (glioblastoma multiforme) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.

AG (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma NOS (not otherwise specified)) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.

Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.

Tandutinib 500 mg by mouth daily dose twice a day.

MLN-518 (Tandutinib)

Forty-five one-sentence questionnaire to assess health related quality of life in patients with brain cancer.

Quality-of-life assessment

Howard Fine, M.D.

Background:

In order to survive, brain tumors must have a network of blood vessels to supply it with oxygen and nutrients. The tumors produce substances that enable new blood vessels to form.

Tandutinib and Bevacizumab are experimental drugs that may prevent new blood vessel formation and thereby slow or stop tumor growth in the brain.

Objectives:

To determine the safety and side effects of Tandutinib in combination with Bevacizumab in patients with brain tumors.

To evaluate the response of brain tumors to treatment with Tandutinib and Bevacizumab.

Eligibility:

Patients 18 years of age and older with a malignant brain tumor for whom standard treatments (surgery, radiation and chemotherapy) are no longer effective.

Design:

Patients receive treatment in 4-week cycles as follows: Tandutinib by mouth twice a day every day and intravenous (through a vein) infusions of Bevacizumab over 90 minutes (or less if well tolerated) every 2 weeks. Treatment may continue for up to 1 year, and possibly longer, as long as there are no signs of tumor growth or serious treatment side effects.

Patients are evaluated with magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scans before starting treatment and then periodically to determine the response to treatment.

Patients have physical and neurological examinations every 4 weeks and blood tests every 2 weeks. They complete quality of life questionnaires every 4 weeks.

Background

Bevacizumab is a monoclonal antibody directed against vascular- endothelial growth factor (VEGF), the major angiogenesis factor involved in high-grade glioma-mediated angiogenesis. Preclinical studies in our laboratory and others have shown potent antiglioma activity in vivo and early clinical trials of bevacizumab in combination with irinotecan and alone (National Institutes of Health (NIH) study) have demonstrated significant anti-vascular permeability and anti-glioma effects in patients with recurrent gliomas.

Tandutinib (MLN518) along with bevacizumab represents an attempt to further capitalize on the concept of targeting the tumor vasculature. Tandutinib is a small molecule inhibitor of fms-like tyrosine kinase receptor-3 (FLT3), platelet derived growth factor receptor (PDGFR), and cKIT (type III receptor tyrosine kinases). It has demonstrated anti-leukemic activity in patients with relapsed and refractory acute myeloid leukemia (AML) whose blasts contain an activating internal tandem duplication mutation of FLT3. However, in this study tandutinib is being added to bevacizumab primarily for its activity against the PDGFR and cKIT. Hannahan and colleagues have demonstrated the additional anti-tumor activity that results in vivo with combined inhibition of the vascular endothelial growth factor receptor (VEGFR) and PDGFR. The activity of PDGFR inhibition is hypothesized to result from its effect on pericytes, the cells that surround and support endothelial cells. These cells have abundant expression of PDGFR and require platelet-derived growth factor (PDGF)-PDGFR interaction for their normal function.

Objectives

To establish data regarding the anti-tumor activity of the combination of bevacizumab and tandutinib in patients with recurrent high-grade gliomas, as determined by progression-free-survival.

Eligibility

Patients with histologically proven recurrent malignant glioma are eligible for this study.

Design

Patients will receive tandutinib as a single agent at a daily dose of 500 mg PO bid for the first 14 days of treatment. Radiology: Prior to the first dose of tandutinib patients will undergo an MRI-perfusion scan and an FDG-PET scan. An MRI-perfusion scan will then be repeated between days 12-14 of the first 14 days of tandutinib monotherapy. On day 15, treatment with bevacizumab will be added to the ongoing treatment with tandutinib. Bevacizumab will be given intravenously in a dose of 10 mg/kg, repeated once every 2 weeks. After completion of the first 4 weeks of combined tandutinib and bevacizumab therapy (6 weeks after initiating treatment with tandutinib) considered the first cycle of therapy) the MRI-perfusion and fludeoxyglucose 18F-positron emission tomography (FDG-PET) scans will be repeated before the next dose of bevacizumab is given. Patients who are clinically/neurologically stable, and who have radiographically stable or responding disease at the end of that first cycle and every cycle thereafter (every 4 weeks), will continue treatment with tandutinib and bevacizumab. Magnetic resonance imaging (MRI)-perfusion scans will be repeated after the completion of every 4 weeks of therapy. A total of 80 patients will be enrolled to this study (GBM (glioblastoma multiforme)=40, AG=40)

Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors

A Phase 2 Trial of Tandutinib in Combination With Bevacizumab for Patients With Recurrent High-Grade Gliomas

Percentage of participants with progression free survival at 6 months. Progression is defined as a 25% increase in the sum of all measurable lesions (or two largest lesions if too numerous) over the smallest sum observed (over baseline if no decrease), clear worsening of any evaluable disease, appearance of any new lesion/site, or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Tandutinib & Bevacizumab in GBM Patients

AG (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, and malignant astrocytoma NOS (not otherwise specified )) Tandutinib 500 mg by mouth daily dose twice a day. Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks

Tandutinib & Bevacizumab in AG Patients

Dr. Katherine Warren

Progression-free Survival at 6 Months

Irinotecan

Topoisomerase I Inhibitors

Enzyme Inhibitors

All patients are treated with nanoliposomal CPT-11

Depending on UGT1A1 genotyping status, patients are either given a starting dose of 120 mg/m\^2 (wild type) or 60 mg/m\^2 IV q3 weeks.

Nanoliposomal CPT-11

Michael Prados, MD

This is a Phase I study of Nanoliposomal CPT-11 in patients with Recurrent high-grade gliomas. Patients must have a histologically proven intracranial malignant glioma, which includes glioblastoma multiforme (GBM), gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified). Patients who are wild type or heterozygous for the UGT1A1\*28 gene will received Nanoliposomal CPT-11. The total anticipated accrual will be approximately 36 patients (depending upon the actual MTD). The investigators hypothesis is that this new formulation of CPT-11 will increase survival over that seen in historical controls who have recurrent gliomas because CPT-11 will be encapsulated in a liposome nanoparticle, which has been seen to reduce toxicities from the drug.

Patients with recurrent malignant glioma will receive Nanoliposomal CPT-11 at the time of relapse. The dose will be adjusted according to a phase-1 dose escalation scheme. Patients will receive drug intravenously every 3 weeks until tumor progression or excessive toxicity. Weekly follow up will occur to assess toxicities during the DLT phase of the trial. Patients will have different dose escalation if UGT1A1 is 6/6 versus UGT1A1 is 6/7. Patients with UGT 1A1 of 7/7 will not be eligible. All patients must have UGT 1A1 status know as an eligibility requirement. Patients will be followed for both toxicity and progression, and progression will be evaluated by MR imaging every 6 weeks. Pharmacokinetics will be obtained in the first treatment cycle.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 2 Trial Using Talampanel in Patients With Recurrent High Grade Gliomas	NCT00062504	Glioblastoma Mu... Anaplastic Astr... Anaplastic Olig... Anaplastic Mixe...	Talampanel	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.
Phase 2 Trial Using Talampanel in Patients With Recurrent High Grade Gliomas	NCT00062504	Glioblastoma Mu... Anaplastic Astr... Anaplastic Olig... Anaplastic Mixe...	Talampanel	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.
A Randomized Phase II Trial of Vandetanib (ZD6474) in Combination With Carboplatin Versus Carboplatin Alone Followed by Vandetanib Alone in Adults With Recurrent High-Grade Gliomas	NCT00995007	Glioblastoma Mu... Gliosarcoma Anaplastic Astr... Anaplastic Olig... Anaplastic Mixe...	ZD6474 (Vandeta... Carboplatin	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Phase 2 Trial Using Talampanel in Patients With Recurrent High Grade Gliomas	NCT00062504	Glioblastoma Mu... Anaplastic Astr... Anaplastic Olig... Anaplastic Mixe...	Talampanel	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.
Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors	NCT00667394	Glioblastoma Gliosarcoma Anaplastic Astr... Anaplastic Olig... Anaplastic Mixe...	Bevacizumab MLN-518 (Tandut... Quality-of-life...	18 Years -	National Institutes of Health Clinical Center (CC)
A Phase I Trial of Nanoliposomal CPT-11 (NL CPT-11) in Patients With Recurrent High-Grade Gliomas	NCT00734682	Glioblastoma Gliosarcoma Anaplastic Astr... Anaplastic Olig...	Nanoliposomal C...	18 Years -	University of California, San Francisco
Phase 2 Trial Using Talampanel in Patients With Recurrent High Grade Gliomas	NCT00062504	Glioblastoma Mu... Anaplastic Astr... Anaplastic Olig... Anaplastic Mixe...	Talampanel	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.

Spots Global Cancer Trial Database for anaplastic mixed oligoastrocytoma