Clinical Trial Update- Arsenic Trioxide (ATO) with Radiation in the Newly Diagnosed (Phase 1)

On March 3^rd, the Journal Neuro-Oncology electronically published the results of the phase 1 trial using arsenic trioxide (ATO) in combination with radiation for newly diagnosed pediatric high-grade gliomas.   This phase 1 trial, exclusively opened at Johns Hopkins (primary investigator Kenneth Cohen), was first submitted to clinicaltrials.gov in November 2004 and was completed in January 2011.    As a phase 1, the aim was to determine toxicity and dosing information--not effectiveness against the tumor.  

Rationale:   Arsenic trioxide affects cells in a different way than radiation.   In mice, ATO has shown destruction of the tumor vasculature and near-complete blockage of blood flow to the tumor.   This has resulted in central tumor death (necrosis).   The hope was that ATO would kill the poorly perfused, hypoxic, radio-resistant areas of a tumor while radiation would kill the tumor in well-oxygenated areas.

Format:  The format was to have groups of 3-6 patients receive escalating doses of arsenic trioxide until the MTD was established.  Each child received radiation once daily for 5 days a week for 6 weeks.  A child also received arsenic trioxide over 1 hour with radiation.   The first group received the ATO only once a week.  Each subsequent group had another day of the week added until the last group received ATO with every radiation treatment.  A total of 24 children entered the trial.   Those that progressed during radiation or family chose to stop treatment was removed from the study.  Twenty-one children had evaluable results. 

Results:  The trial included 12 DIPGs, 4 AAs and 5 GBMs.  Because children could receive additional therapy after 30 days from radiation, no response assessment was done.   The study does note that all children died of their tumor.   With DIPG the median time to death was 10 months (range 2-22 months).    There was no dose limiting toxicity.

Conclusion:  The article concluded that arsenic trioxide could be given with each radiation treatment.

 Interestingly, the article states that there have been a number of recent preclinical studies that have shown an effect on cancer stem cells trough an effect on Notch and Sox2.   Other research has shown that the hedgehog pathway might be antagonized and thus be helpful in other tumors as well (such as Sonic hedgehog driven medulloblastomas).  Although there is one adult glioma study using arsenic trioxide in combination with temozolmide and radiation on clinicaltrials.gov, there are no pediatric glioma studies open using arsenic trioxide.    The question now is whether there will be a phase 2 trial.

For those families that participated in this trial- thank you.   This work provides important information to move forward in trying to find a cure for DIPG.  Even if it doesn't provide the cure hope for, research tends to stimulate research.  There is much, much more research into DIPG than when when this study initially opened in late 2004.  People are searching for a cure.

References:

A phase 1 trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood

http://www.ncbi.nlm.nih.gov/pubmed/23460318

Arsenic Trioxide and Radiation Therapy in Treating Young Patients with Newly Diagnosed Gliomas

http://clinicaltrials.gov/ct2/show/NCT00095771?term=arsenic+trioxide+glioma&rank=3

The Clinical Trial Process

http://www.dukehealth.org/health_library/health_articles/the_clinical_trial_process