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AzTrials

Glioblastoma MultiformePhase 2NCT00995007

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

A Phase 2 study testing ZD6474 (Vandetanib) and Carboplatin in people with Glioblastoma Multiforme and Gliosarcoma, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 100 years
What is being tested?
ZD6474 (Vandetanib) and Carboplatin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
112 participants
Where
1 siteUnited States
Study dates
Sep 2009to Dec 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 100 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with histologically proven malignant primary gliomas who have progressive disease after radiotherapy will be eligible for this protocol. These include glioblastoma multiforme (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), and malignant glioma/astrocytoma NOS.
  • Patients must have an magnetic resonance imaging (MRI)/computed tomography (CT) scan performed within 14 days prior to registration and on a fixed dose of steroids for at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline MRI/CT is required. The same type of scan, that is, MRI or CT must be used throughout the period of protocol treatment for tumor measurement.
  • Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:
  • Patients will be eligible four weeks after surgery if they have recovered from the effects of surgery.
  • Residual disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual disease post-operatively, a CT/MRI should be done:
  • no later than 96 hours in the immediate post-operative period or
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  • at least 4 weeks post-operatively, and
  • within 14 days of registration, and
  • on a steroid dosage that has been stable for at least 5 days.
  • If the 96 hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days.
  • Patients must have failed prior radiation therapy.
  • All patients or their previously designated durable power of attorney (DPA) (if the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) must sign an informed consent indicating that they are aware of the investigational nature of this study.
  • Patients must be greater than or equal to 18 years old, and must have a life expectancy greater than 8 weeks.
  • Patients must have a Karnofsky performance status of greater than or equal to 60.
  • Patients must be at least six weeks from radiation therapy. Additionally, patients must be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from procarbazine, and 2 weeks from last vincristine administration. Patients must be at least 4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen) including investigative agents.
  • Patients must have adequate bone marrow function (white blood cell (WBC) greater than or equal to 3,000/microL, absolute neutrophil count (ANC) greater than or equal to 1,500/mm(3), platelet count of greater than or equal to 100,000/mm(3), and hemoglobin greater than or equal to 10 gm/dl), adequate liver function (aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase 2.5 less than or equal to upper limit of normal (ULN) and bilirubin less than or equal to 1.5 times ULN), and adequate renal function (creatinine less than or equal to 1.5 mg/dL and/or creatinine clearance greater than or equal to 60 cc/min) before starting therapy. Patients must also have serum potassium greater than or equal to 3.5 mg/dL, magnesium greater than or equal to 0.75 mmol/L and calcium levels within normal levels; supplementation is allowed. In cases where the serum calcium is below the normal range, 2 options would be available: 1) 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. 2) Determine the ionized calcium levels. Exclusion is then to be based if these ionized calcium levels are out of normal range despite supplementation. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
  • Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.
  • This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race. Minorities will actively be recruited to participate.
  • Patients must not be pregnant or nursing, and all patients (both men and women) must be willing to practice birth control during and for 2 months after treatment with vandetanib and/or carboplatin. Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test. In addition, WCBP patients must agree to use adequate contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner).
  • A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with corrected QT interval (QTc) less than 480 msec. If a patient has a QT interval corrected for heart rate using Bazett's) QTcB interval > 480 ms on screening ECG, the screening ECG may be repeated twice [at least 24 hours apart] for a total of 3 ECGs. The average QTcB from the 3 screening ECGs must be less than or equal to 480 ms in order for the patient to be eligible for the study).

Who cannot join

  • Patients who, in the view of the treating physician, have significant active hepatic, renal, or psychiatric diseases are ineligible.
  • Prior treatment with vandetanib.
  • Prior treatment with platinum-based therapy.
  • Patients known to have an allergic response to mannitol.
  • Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome (SVC), New York Heart Association (NYHA) classification of heart disease greater than or equal to 2 within 3 months before entry; or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
  • History of arrhythmia (multifocal premature ventricular contractions PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events (CTCAE) grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded.
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  • QTc prolongation with other medications that required discontinuation of that medication.
  • Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age.
  • Presence of left bundle branch block (LBBB.)
  • QTc with Bazett's correction that is unmeasurable, or greater than or equal to 480 msec on screening ECG. (Note: If a subject has a QTc interval greater than or equal to 480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than 480 msec in order for the subject to be eligible for the study. Patients who are receiving a drug that has a risk of QTc prolongation excluded if QTc is greater than or equal to 460 msec.
  • Any concurrent medication that may cause QTc prolongation or induce Torsades de Pointes. Drugs listed in Appendix E, Table 2, that in the investigators opinion cannot be discontinued are allowed; however, must be monitored closely with additional ECGs and laboratory assessments of electrolytes to ensure the patients safety.
  • Concomitant medications that are potent inducers (rifampicin, rifabutin, St. Johns Wort and Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs) of cytochrome P450 3A4 (CYP3A4) function. EIAEDs are allowed.
  • Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg)
  • Currently active diarrhea that may affect the ability of the patient to absorb the vandetanib or tolerate diarrhea.
  • Women who are currently pregnant or breast feeding.
  • Patients known to have a malignancy (other than their malignant glioma) that has required treatment in the last 12 months and/or is expected to require treatment in the next 12 months (except for non-melanoma skin cancer, carcinoma in situ in the cervix or ductal carcinoma in situ).
  • Invasive procedures defined as follows:
  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy
  • Anticipation of need for major surgical procedures during the course of the study
  • Core biopsy within 7 days prior to Day 1 (D1) therapy
  • Patients should not be on anti-platelet medications (aspirin, clopidogrel, ticlopidine, prasugel). Non-steroidal anti-inflammatory drugs should be used with caution if medically necessary.
  • Restrictions
  • Patients who are blood donors should not donate blood during the trial and for 3 months following their last dose of trial treatment.
  • Due to the experimental nature of vandetanib, all patients of childbearing potential must be one year post-menopausal, surgically sterile, or using an acceptable method of contraception (oral contraceptives, barrier methods in conjunction with spermicide,
  • approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal ligation) during and continued after the last dose of study medication. Contraceptive use will continue for at least two months, five half-lives, after the last dose on study medication.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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.
Read more

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.
Read the detailed description

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.

Being tested
ZD6474 (Vandetanib), Carboplatin
Keywords
Brain Tumor, Chemotherapy, Antiangiogenesis, Radiation, Progression, Glioma, Glioblastoma Multiforme
Medical subject headings
Glioblastoma, Gliosarcoma, Astrocytoma, Oligodendroglioma, Brain Neoplasms, Disease Progression, Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ZD6474 (Vandetanib)Drug

    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.

  • CarboplatinDrug

    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.

Study groups in NCT00995007
Study groupRoleWhat they receive
Group 2Active comparatorSequential Group (carboplatin followed by vandetanib)
Receives: Drug: ZD6474 (Vandetanib); Drug: Carboplatin
Group 1Active comparatorCombo Group (both drugs together)
Receives: Drug: ZD6474 (Vandetanib); Drug: Carboplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free Survival at 6 Months

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

    Measured: 6 months

Secondary outcomes (2)

  1. Overall Survival

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

    Measured: Time between the first day of treatment and the day of death, up to 1.5 years

  2. Number of Participants With Adverse Events

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

    Measured: 70 months and 19 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Oct 2009 (estimated)
  2. Study startSep 2009
  3. Primary completionJun 2015
  4. Study completionDec 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
112 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00995007
Sponsor's protocol ID
090222
Other IDs
09-C-0222
Status last verified
Feb 2016
First submitted
10 Oct 2009
Last updated
29 Mar 2016
Data monitoring committee
No

Publications

  • Prados MD, Schold SC Jr, Fine HA, Jaeckle K, Hochberg F, Mechtler L, Fetell MR, Phuphanich S, Feun L, Janus TJ, Ford K, Graney W. A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro Oncol. 2003 Apr;5(2):96-103. doi: 10.1093/neuonc/5.2.96.

    PubMed 12672281

  • Prados MD, Warnick RE, Mack EE, Chandler KL, Rabbitt J, Page M, Malec M. Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial. Am J Clin Oncol. 1996 Dec;19(6):609-12. doi: 10.1097/00000421-199612000-00016.

    PubMed 8931682

  • A randomized phase II trial of Vandetanib (ZD6474) in combination with carboplatin versus carboplatin alone in adults with recurrent glioblastoma. Katherine McNeill, Fabio Iwamoto, Teri Kreisl, Joohee Sul, Joanna Shih, Howard Fine, New York University, New York, NY, USA, Columbia University, New York, NY, USA, National Institutes of Health, Bethesda, MD, USA, Food and Drug Administration, Silver Spring, MD, USA.

  • A randomized phase II trial of Vandetanib in combination with carboplatin versus carboplatin alone followed by Vandetanib aline in adults with recurrent anaplastic astrocytoma. Prakash Ambady, Katherine Warren, Joanna Shih, Teri Kreisl, Howard Fine, National Institutes of Health, Bethesda, MD, USA.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing ZD6474 (Vandetanib) and Carboplatin in people with Glioblastoma Multiforme and Gliosarcoma, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Mar 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression Free Survival at 6 Months (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00995007, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Mar 2016.

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