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- Imetelstat for Refractory/Recurrent Pediatric Brain Tumors

A new Pediatric Brain Tumor Consortium phase 2 trial using a telomerase inhibitor, Imetelstat also known as GRN163L,   for recurrent or refractory DIPG (as well as three other recurrent or refractory pediatric brain tumors) just went up on clinicaltrials.gov this week.   This two section component study will be both a phase 2 study as well as a molecular analysis study.   DIPGs will be excluded from the molecular analysis study component of this trial and will not require tissue/histological confirmation.  The protocol will include a two hour IV infusion on day 1 and 8 followed by repeat infusions every 21 days for two years.

What are telomeres?  I think of them like the plastic coating at the end of shoelaces which keeps the laces from fraying out. 

Telomeres are thought to be an important in keeping a cell's DNA intact.    They are located on the end of chromosomes and shorten with cell divisions.   This shortening of telomeres protects the inner DNA as if it wasn't there the DNA could be affected.   One can actually see how these telomere are at the end of chromosomes (image).   When the telomeres in normal cells become too short the cell stops dividing and dies.   However,  there is an enzyme called telomerase which adds some bases to the end of telomeres to keep them from getting too short.  This can be present in normal young cells; but is seems to be more prevalent in cancer cells.  It is thought that telomerase might be one of the things that allows cancer cells to keep dividing and not die out. 

For those that are interested in getting some background on telomeres check out these two article...
*New Telomere Discovery Could Help Explain Why Cancer Cells Never Stop Dividing
*Are Telomeres the Key to Aging and Cancer?

The hope is that if one can block telemorase activity in cancer that these cells will die out.   

For those interested in work that has been done in pediatric brain tumors with telomeres/telomerase, check the work of Uri Tabori (Sick Kids) who published work about telomeres in pediatric low grade gliomas back in 2006 and ependymomas in 2008.  In addition, St Jude made a study available in the end of 2012 using whole-genome sequencing to look at telomere content in pediatric cancer.

The Pediatric Brain Tumor Consortium (PBTC) is a group of US institutions banded together first in 1999 with the goal of improving treatment/outcomes with children with primary brain tumors by "rapidly conducting novel phase 1 and 2 clinical trials of new therapeutic drugs, new biological therapies, treatment delivery technologies and radiation treatment strategies in children" and a second goal of "characterizing reliable markers and predictors of response to new therapies".   At this time there are 11 full members and 4 temporary members of the PBTC.  Currently the PBTC is running 5 open trials of which two are related to DIPG- one is this trial and the other is ABT-888/temozolomide trial for newly diagnosed kids with DIPG.  The primary investigator for this Imetelstat trial is Maryam Fouladi (Cincinnati).  Contact information is available on the references below.

Reference:
A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma, Medulloblastoma/Primitive Neuroectodermal Tumor and Diffuse Intrinsic Pontine Glioma
http://clinicaltrials.gov/ct2/show/NCT01836549?term=dipg&rank=24

Protocol Summary for Parents from PBTC
http://www.pbtc.org/public/PBTC-036_v1_1%20Summary%20for%20patients%20and%20families.pdf

Protocol Summary for Health Care Providers from PBTC
http://www.pbtc.org/public/PBTC-036%20Protocol%20Abstract%20and%20Schema%20for%20health%20prof_v3.pdf

COG Phase 1 Imetelstat Trial in Young Patients (appears to still be recruiting)
http://clinicaltrials.gov/ct2/show/NCT01273090?term=imetelstat&rank=6

Genomic Landscape of treatment-naive DIPG Biopsy Sample

Yesterday I posted about the first International DIPG conference held in 2009 in Barcelona, Spain.  During that conference,  Dr. Jaume Mora moderated a two hour session discussing proposals for common international/interdisciplinary DIPG research agenda items.    Many things seems to be evolving collaboratively in the European DIPG arena.  The action points of the 2012 Barcelona meeting are impressive (click here to see).

In looking at the SNO/PBTF Pediatric Neuro-Oncology Basic Science and Translational  Research Conference abstracts, I noticed a somewhat unusual abstract.   This abstract (to me) highlighted the internationally collaborative nature of DIPG research today.   The authors were from 4 countries- France, England, Spain and Canada (Vancouver)!

This abstract examined the whole genome sequencing of 20 pre-treatment DIPG samples (all high grade gliomas) obtained by stereotactic biopsy in France.

Although the abstract word limits don't allow for in-depth understand of the work, there were some interesting things.  First,  the K27M mutations was seen in all cases.

It would seem that there were some cases where the initial untreated specimen was compared with a post-mortem sample.   Not really unexpected, the autopsy sample has increased number of mutations.  The authors write conclude that DIPG biopsy provides an opportunity to study the genome and identify possible intervention targets.

Something more fascinating to me - and not part of the abstract - is the question of how did these researcher get together to do this research for this abstract.   I believe the children from Spain might be offered the option of going to France for biopsy.   I believe that the children in the UK were offered that in that past as well.   In addition, Chris Jones was tasked as the responsible member for the biopsy biological studies (for SIOP-E DIPG Network).   In his Barcelona 2012 presentation, Chris Jones talked about "What to Do With Tissue".  In this, he did mention transatlantic collaboration.  

The thing that I wonder about though- is British Columbia.   Sick Kids has been a powerhouse of DIPG research out of Canada.   It would seem that Vancouver might be a place to watch as well.

Reference:
The Genomic Landscape of treatment-naive DIPG Biopsy Sample
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=738496

DIPG Around the World: Spain and DIPG

For me, the DIPG community started to come together in Barcelona, Spain in February 2009.  Eleven pioneering,international researchers came together in Barcelona, Spain to try to figure out new ways to fight this devastating pediatric cancer.   It is also a time when advocacy foundations started to work together specifically on DIPG.  The Alicia Pueyo Foundation funded this conference and the Musella Foundation in conjunction with Just One More Day made videos available of the presentations.  These videos are still available today (click here).

Many of the names that were at that first conference are mentioned frequently in the DIPG community- Hargrave (UK), Kieran (Boston), Caretti(at that time Netherlands but now in Michelle Monje's lab), Van Vuurden (Netherlands),  Gururangan (Duke) and Broniscer (St. Jude).  

I'm not sure why the other names are not as well known.  It certainly has been a significant and unfortunate oversight that the Spanish researchers and doctors who initiated the cascade of events that we have seen unfold over the last four years are not as well recognized as these other names.   Today I hope to rectify some of that.

So those names back in 2009:
OFELIA CRUZ (Barcelona)  -Diffuse brainstem glioma: a clinical introduction
SEBASTIA PONS (Barcelona)- Brainstem embryology/ brain precursor cells
JOAN SEOANE (Barcelona) - Molecular gliomagenesis: genes and pathways
MANUEL RAMIREZ (Madrid)- Gene therapy strategies
In addition, Dr Jaume Mora moderated a two hour session discussing proposals for a common international/interdisciplinary research agenda!

Spain didn't just get the ball rolling on DIPG, but they have also continued to push forward in various aspects of DIPG research and treatment.   Perhaps the most visible accomplishment was the 2012 Barcelona conference.  Again the European DIPG participants made the presentations available.  In this meeting Spain had five different presentations-
*Biopsy and Autopsy (Mora)
*Intra-arterial Chemotherapy (Sola)
*Oncolytic Adenovirus for DIPG (Alonso)
*Intra-tumoral delivery of Oncolytic Adenovirus (Carcaboso)
*Irinotecan/Cisplatin Clinical Trial (Cruz)

The Irinotecan/Cisplatin trial started spring 2012.   Because of a keyword issue, it might be hard to find as it is listed under brain stem tumor, brainstem glioma and intrinsic brain stem tumor (but not DIPG or pontine glioma).

Clearly Spain has been a major factor in the advancement of DIPG Research.   Thank you for making this happen.

Much of the DIPG work in Spain has been funded by the Alicia Pueyo Foundation.   You can site a listing of their projects on their site.