In this part we discuss new methods that undergo a clinical trials in brain tumor treatment.
Clinical Trials Basics
Clinical trials are used to test new methods, devices and procedures on people. This also serves to determine the efficiency and safety of new research methods. Each trial needs a protocol or action plan as well as participants to be conducted. Participants are chosen based on their medical background related to the new study that is to be tested. The following website provides a database for federal and private clinical trials around the world, but with focus on North America: www.clinicaltrials.gov (maintained by the U.S. National Library of Medicine). Searching for interventional studies with results regarding brain tumor treatment offers 325 studies (from May 29th), distributed across the world as shown in the map.
Figure 1: distribution of clinical trials with results regarding brain tumor treatment, according to the U.S. National Library of Medicine database [5]
Clinical trials are separated into 5 phases [1]:
- Phase 0 is for examining if the drug works as expected. The number of patients is very small (around a dozen).
- Phase 1 is for examining how high the dose of the drug should be for the expected outcome and if the drug is safe. The number of patients is around several dozen.
- Phase 2 is for examining less-common side-effects, therefore larger groups of up to 100 patients are chosen.
- Phase 3 is for examining if the new drug yields the same or less benefits than the standard treatment. Placebos may be used and at least several hundred patients participate in a phase 3. trial. At the end of a phase 3 trial, the new drug may be approved by the Food and Drug Administration (FDA), if it is more effective and/or safer than the standard treatment.
- Phase 4 is for examining long-time effects and rare side-effects after the drug is prescribable to patients.
New methods undergoing clinical trials
Looking at the conventional methods, newly established methods and newly researched methods, it becomes clear that many trials address the possible impact of one drug or the combination of several drugs to brain tumors. Many trials also examine a combination of the multitude of already existant methods.
Method 1
In the following we will have a look at a specific ongoing trial called "Phase I/II Study of ZD6474 (Vandetanib) With Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients With Newly-Diagnosed Glioblastoma" [2].
Overview: This trial is divided in two phases. In the first phase the safety of combining ZD6474 (Vandetanib) with standard therapy for glioblastomas and gliosarcomas, temozolomide (Temodar) and radiation therapy is determined. To define safety, the highest possible dose for ZD6474 (Vandetanib) in this treatment scenario is determined. In the second phase, the efficiency of this treatment combination is tested. Primary outcome measures are the number of participants that experienced a dose-limiting toxicity (DLT) in a time frame of two years and the median overall survival (OS) of Phase II patients in a time frame of three years. Secondary outcome measures are the Median Progression-free Survival (PFS), as calculated by the number of months patients remain progression-free in a time frame of three years as well as further evaluating the safety profile of ZD6474 (Vandetanib) and defining the safety of ZD6474 (Vandetanib) with radiation therapy and concomitant and adjuvant temozolomide.The trial started in May 2007 and is estimated to be completed in December 2017.
Background: Radiation therapy and the use of temozolomide is the standard treatment for glioblastomas and gliosacromas. The uncontrolled tumor growth of these tumors could be caused by an excess of cell growth factors and their receptors, according to research. Therefore this study examines the drug Vandetanib that is designed to block the way to the growth factors vascular endothelial growth factor (VEGF) and the epidermal growth factor (EGF). This blocking could reduce the blood supply to the tumor and therefore slow down the tumor growth. Laboratory studies also indicated that this drug enhances the sensitivity of glioblastomas to radiation therapy.
Approach: For the trial the participants were divided into two groups (also called "arms"). Arm A received temozolomide and radiation therapy in the "Induction Phase" and was treated with temozolomide in the "Maintainance" Phase. In addition to this treatment, Arm B received Vandetanib in the "Induction" Phase.
Results: Overall 111 people participated in the clinical trial. Until now no statistical analysis for the pre-defined outcome measures are provided. The two following tables (outcome measure 2 & 3) might indicate a slight improvement of the therapy by including Vandetanib.
However the table results provided in [2] also show that the percentage of adverse events for participants who were treated with Vandetanib slightly increased. So the final result of this study would have to define a trade-off in security and efficiency.
Method 2
The following study is called "A Study of MEDI-575 in Subjects With Recurrent Glioblastoma Multiforme". [3]
Overview: The study is a Phase II study that examines the usefulness of the drug MEDI-575 with patients that started being treated with after the first recurrence of glioblastoma multiforme. It is an interventional study without masking, the primary outcome being the progression-free survival rate of the patients at six months. Progression was defined as at least 25% increase in tumor mass. The examined secondary outcome consists of multiple factors: best overall response, time to response, duration of response, time to progression, participants with treatment adverse effects and others. The corresponding timeframes for the secondary outcome factors differ and are up to 21 months. The study started in January 2011 and was completed in November 2012 with 56 initial participants
Background: MEDI-575 is a monoclonal antibody, therefore this treatment can be classified as a immunotherapy. [4] As a Phase II study, it primarily focuses on evaluating the activity, safety and pharmacology of MEDI-575.
Approach: The study is performed as a multicenter, single-group (i.e. single-arm) study. The patients receive MEDI-575 as a 60 min intravenous infusion every day for 21 days. The patients withdraw from the study in case of tumor progression, initiation of alternative anticancer therapy, unacceptible toxicity or personal reasons.
Results: Of the 56 initial participants, 13 completed the trial. Of the 43 that did not complete the trial, 1 was lost to a follow-up, 12 withdrew and 30 died. Table 3 shows the primary outcome: of the 56 participants, 15.4% survived progression-free at 6 months.
Table 3: primary results of "A Study of MEDI-575 in Subjects With Recurrent Glioblastoma Multiforme"
