Capecitabine Phase 1 Trial Publication

As a dose-escalating phase 1, this trial's main objective was to establish the maximum tolerated dose and toxicity of capecitabine (Xeloda) in a pediatric population (between the ages of 3 and 21).   The drug was given for nine weeks in two daily doses from the start of radiation.   There was then a two week break followed by another 3 cycles of capecitabine in which the drug was given twice daily for two weeks followed by a one week break.

From a parent perspective, a very cool thing about capecitabine is that this flavored, film coated, rapidly disintegrating tablet did not have to be swallowed intact but could be disolved in water.   There have been other studies where the younger patients were excluded because of the inability to swallow pills intact.

The way capecitabine works is that it is a pro-drug and can be broken down to 5-fluorouracil (5-FU) by a cellular enzyme thymidine phosphorylase (TP).  TP is found at significantly higher levels in many cancers.   Only 5-FU has antiproliferative properties.   The hope is that then the active metabolite 5FU will concentrate specifically in the tumor cells.  In addition, radiation induces the enzyme TP.   

5 FU has been around as a antimetabolite chemotherapy on its own since it was patented in the late 1950's.  The way it works is that 5 FU blocks an enzyme (thymidylate synthase inhibitor) which allows the cell to make a protein that is needed for DNA.   Without this, cells can not make new DNA needed for cell division and thus undergo a "thymineless death".

Since TP has been found in increased level in gliomas, it was thought that a combination of capecitabine and radiation could be a way to attack pediatric DIPGs and high grade gliomas.    Of note, capecitabine has been effective for breast cancer brain metastases.

Of the 24 enrolled kids, 15 patients had DIPG.  The dose-limiting toxicity included grade 2 and 3 palmar/plantar erythroderma and grade 2 and elevation of a liver enzyme alanine aminotransferase.

This trial (PBTC-021) was run from at the institutions of the Pediatric Brain Tumor Consortium. Interestingly, the phase 2 (PBTC-30) has also finished patient accural.   .  Although the hope of radiosensitizers in general for DIPG have not lived up to expections, this radiosensitzer seems to have other effects which perhaps might have increased effectiveness.   The phase 2 is expected to complete data collection in June 2013.   Hopefully,  meeting abstracts or publication will follow shortly thereafter.

References:
Phase I trial of capecitabine rapidly disintegrating tablets and con concomitant radiation therapy in children with newly diagnosed brainstem glioma and high-grade gliomas
http://www.ncbi.nlm.nih.gov/pubmed/

Capecitabine therapy of central nervous system metastases from breast cancer
http://www.ncbi.nlm.nih.gov/pubmed/17611719

Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report
http://www.ncbi.nlm.nih.gov/pubmed/16800978

New Trial Pending: Reirradiation for DIPG

Every once in awhile I will just randomly go through clinicaltrials.gov searching to see if anything new has been put up.   I had gone through a few times recently seeing two reirradiation trials listed- one open and one not yet open.   Knowing of the MD Anderson trial I thought it was just a computer glitch.   When I finally opened the page, it was a surprise it wasn't MDA but a trial based in Israel.  

It not that Israel hasn't come up before in the brain tumor community.   It definitely has.  There has been interest in the Newcastle Disease oncolytic virus and the Novocure device on internet groups to which I belong.   However, both have had issues that made it problematic in the DIPG community.   In the former lack of a tissue diagnosis could be a hurdle and the latter has significant issues with pad placement for electrical fields have made the device not possible- at least not yet.   It is just that Israel isn't one of the places that is often mentioned in DIPG work.

It would certainly seem that this pending trial was based on the MD Anderson work published last year (abstract link below).   In that pilot project 4 of 6 children had significant clinical improvement after  receiving re-irradiation at symptom progression.   Three of these children were able to walk again after re-irradiation.   The mean progression free survival was 5 months.  Those children with the longest time interval between radiation courses had the greatest benefit.

This trial is interesting it is allowing for a short interval for radiation at a minimum of 4 months.  Since at one time it was thought that re-irradiation wasn't even possible is is a huge shift in thinking.  

Another interesting thing is the increased specifics on the inclusion criteria-
-diagnosis of DIPG based on short classic history,
-clinical signs (long tract signs, cranial nerve deficits and ataxia), and
-classic MRI features (more than 2/3 of the tumor is located within the pons and tumor encompasses more than 60% of the pons).

I think we are going to increasingly see this type of specific DIPG definition be articulated in trial inclusion criteria.   It is important to be able to better interpret results.

The increasing international inertia to fight DIPG is palpable.  It is good to see another country join in the fight to try to do something to help these children.

Reference:
Israel- Hadassah Medical Organization
Palliative Re-irradiation for Progressive Diffuse Intrinsic Pontine Glioma (DIPG) in Children
http://clinicaltrials.gov/ct2/show/NCT01777633?term=dipg&rank=3

MD Anderson
Diffuse Intrinsic Pontine Glioma (DIPG) Reirradiation (ReRT)
http://clinicaltrials.gov/ct2/show/NCT01469247?term=dipg&rank=13

Palliative reirradiation for progressive diffuse intrinsic pontine glioma.
Am J Clin Oncol. 2012 Feb;35(1):51-7. 
http://www.ncbi.nlm.nih.gov/pubmed/21297433

New Upcoming New Trial- Vismodegib

A new clinical trial  for DIPG has appeared on clinicaltrial.gov-
Evivedge (Vismodegib) in the Treatment of Pediatric Patients with Refractory Pontine Glioma

This novel phase 2 trial using the oral sonic hedgehog inhibitor agent in DIPG chidren age 3-18 is not yet open but appears that it is in the works at Phoenix Children's Hospital and Helen DeVos Chldren's Hospital.    The interesting thing is that this trial is open to  kids with residual disease after initial therapy  or at the time of recurrence/progression as confirmed by MRI.   It appears that residual disease means more than 10mm of tumor measured on MRI after receiving radiation.    Thus, although this initially appeared to perhaps be a recurrence trial, it seems it will be open to children that have measurable disease immediately following radiation.

Vismodegib (also known of GDC-0449) has been used in clinical trials in adults and children with refractory medulloblastoma in the past.    A portion of medulloblastomas seem to have the sonic hedgehog pathway as a driver.   This seems like this might also be true for DIPG.

This trial sponsored byVan Adel Research Institute.  The Van Adel Research Institute has been highly involved in the Neuroblastoma and Medulloblastoma Translational Research Consortium.  The next meeting of the NMTRC is May 6-7.

Contacts:
Phoenix Children's Hospital (Phoenix, Arizona)
Contact: Sam Chimienti     602-546-0188     schimienti@phoenixchildrens.com
Principal Investigator: Amy Rosenfeld, MD            

Helen DeVos Children's Hospital (Grand Rapids, Michigan)
Contact: Shannon Mackeigan     616-267-1162     shannon.mackeigan@helendevoschildrens.org
Principal Investigator: Albert Cornelius, MD  
Principal Investigator: Giselle Sholler, MD 

References:
Clinical Trial Listing-
http://clinicaltrials.gov/ct2/show/NCT01774253?term=pontine+glioma&rank=8

NMTRC Conference-
http://www.vai.org/about-vai/news-and-events/upcoming-events/NMTRC.aspx

Van Adel Institute-
http://www.vai.org/

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