A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma

The NIH based study lead by Kathy Warren utilizing low dose pegylated interferon for children with newly diagnosed DIPGs recently was published on line ahead of print in the journal Cancer.  The rationale behind this study was the finding that low dose administration of interferon alfa produced” more significant inhibition of angiogenesis-regulating genes, tumor vascularization, and tumor growth compared with the higher intermittent dose schedule. These effects were lost at higher doses, suggesting that metronomic administration of IFNs may have a more robust antitumor effect.”

In this study, 32 children between the ages of 1.8 and  14.8 years (mean 5.3 years) were given pegylated interferon subcutaneously (a shot under the skin) weekly starting 2-10 weeks after radiation until disease progression or unacceptable toxicity.  The idea was to try to have a continuous low dose of inferferon.

There were no grade 4 toxicities and no child stopped interferon because of toxicity.

The overall survival at 2 years was 14.3%  The median time to progression from diagnosis was 235 days, and the median OS from diagnosis was 351 days. 

The authors concluded, “Although low-dose PEG-Intron therapy did not significantly improve 2-year survival in children with DIPG compared with an historic control population, it did delay the time to progression.”

The narrowness of the eligibility criteria in this study is particularly interesting as it shows the advancement in understanding that not all brainstem tumors are the same.   This stricter eligibility criterion seems to be trying to eliminate those tumors that might have an underlying aspect giving it a better prognosis and thus skew the data.  The eligibility criteria defined as:

• Age less than 21 years
• Diffuse intrinsic tumor with epicenter presumed in the pons
• Signal abnormality involving 50% or more of the pons on T2-weighed sequence at diagnosis
• Involvement of the ventral pons
• No expophytic component
• No patients with known or suspected neurofibromatosis type 1

The paper pointed out that the increasing delineation of a DIPG tumor can make it very difficult to compare results with past papers that did not define the patient population in this way.   Those that previously included focal tumors and those with exophytic components might have mistakenly high overall survival statistics.  For those interested in comparing studies analysis of the eligibility criteria is going to be important.

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma Cancer.  2011 Nov 15. doi: 10.1002/cncr.26659. [Epub ahead of print] 
http://www.ncbi.nlm.nih.gov/pubmed/22086404

Call To Action: Criminals Stealing From Our Families Whose Children have Died

This is shocking…..    There are criminals out there just looking around for kids who have died and then claim them as dependents before some families can file.   Those families that have been targeted must then have to prove that their child was actually their child. 

How can something so appalling happen?  How can people get the social security number? 

Well, actually for those in the know it is very easy.   It is the government who made it mandatory for this data to be rapidly available after an individual’s death.  The thought was not bad or evil.   The Death Master File (yes, that is what is called) was meant particularly for financial institutions to try to prevent others from using a dead person’s SSN to gain credit.   In addition, there was a movement toward more transparency.   What wasn’t considered at that time was the ease of information transfer that would come years later with the internet.   Likely it wasn’t considered how genealogy sites would used the Death Master File. 

So, how easily available is this Death Master File available?   Well, one can even get it as a app- http://itunes.apple.com/us/app/ssdmf/id453279465?ls=1&mt=8

Or if you don’t want to go to all that trouble one can just use one of the genealogy sites.

It seems that the DIPG community has been particularly hard hit  with a dozen or more families being hit this year.   Here is an article from Nov 17 the Huffington Post…..  http://www.huffingtonpost.com/2011/11/17/why-thieves-are-stealing-childhood-cancer-victims-identities_n_1093481.html

On Nov 18, Representative Sam Johnson (R- TX) along with seven co-sponsors introduced a bill  to try to curtail this fraud perpetrated on our grieving families.: 

H.R.3475 -- Keeping IDs Safe Act of 2011 
http://thomas.loc.gov/cgi-bin/query/z?c112:H.R.3475:

Please consider calling and writing your Representative to bring awareness to this issue.  
http://www.house.gov/ 

Unfortunately, it might not be possible to close this loophole before the next tax cycle in 2012 so it is likely that many families will continue to be vulnerable to this fraud.

Clinical Trials for the Newly Diagnosed Child with DIPG

A review of  www.clinicaltrials.gov was done on October 20, 2011 to identify which therapeutic trials are currently listed as open for the newly diagnosed child with DIPG.   The following is information on the ten (10) listed trials that were listed as accruing patients as well as one vaccine trial that is yet to open.  Clinicaltrials.gov seems to be often not be up to date on trial status.  If you have interest or questions it might be wise to contact the primary investigator.  Contact information is listed at the bottom of each clinical trial site.  Most US clinical trials for DIPG can be found with the key word “pontine glioma” but some are still listed under “brainstem glioma”. 

*Note- many, if not most clinical trials will not allow you to enter a trial if you have already started treatment. 

 

PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma

Phase 1
ligible age- 18 months- 21 years
Study Chair- Cynthia Wetmore
Location- St Jude (Memphis, TN)
http://clinicaltrial.gov/ct2/show/NCT01393912?term=pontine+glioma&recr=Open&rank=1

Molecularly Determined Treatment of Diffuse Intrinsic Pontine Glioma

Phase 2
Eligible age- 3-18 years
Study Chair- Mark Kieran
Location- when open up to 20 locations- only Boston open on 10/20/11
http://clinicaltrial.gov/ct2/show/NCT01182350?term=pontine+glioma&recr=Open&rank=3

Lenalidomide and Radiation Therapy in High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas 

Phase 1
Eligible age- 1-18 years
Location- NIH (Bethesda, MD)
http://clinicaltrial.gov/ct2/show/NCT01222754?term=pontine+glioma&recr=Open&rank=4


A Study of Bevacizumab Therapy in Patients With Newly Diagnosed High-Grade Gliomas and Diffuse Intrinsic Pontine Glioma 
Phase- not listed
Eligible age- 3-30 years
Study Chair- Maryam Fouladi
Location- Cincinnati and Chicago
http://clinicaltrial.gov/ct2/show/NCT00890786?term=pontine+glioma&recr=Open&rank=5

Cilengitide in Combination With Irradiation in Children With Diffuse Intrinsic Pontine Glioma 

Phase 1
Eligible age- 6 months-21 years
Study Chair. Pierre Leblond
Location- France
http://clinicaltrial.gov/ct2/show/NCT01165333?term=pontine+glioma&recr=Open&rank=7

Phase I Rindopepimut After Conventional Radiation in Children w/ Diffuse Intrinsic Pontine Gliomas 

Phase 1
Eligible age- 3 to 18
Study Chair- Paul Fisher
Location- Stanford (Palo Alto, CA)
http://clinicaltrial.gov/ct2/show/NCT01058850?term=pontine+glioma&recr=Open&rank=8

Vorinostat and Radiation Therapy Followed By Maintenance Therapy With Vorinostat in Treating Younger Patients With Newly Diagnosed Pontine Glioma 

Phase 1/2
Eligible age- 3 to 21 years
Study Chair- Jack Su
Location- COG trial- multiple locations
http://clinicaltrial.gov/ct2/show/NCT01189266?term=pontine+glioma&recr=Open&rank=11


Pilot Study of  Glioma Associated Antigen Vaccines in Conjunction With Poly-ICLC in Pediatric Gliomas
Phase- none listed (listed as a pilot)
Eligible age- 19 months – 20 years
Study Chair- Regina Jakacki
Location- Pittsburgh
http://clinicaltrial.gov/ct2/show/NCT01130077?term=pontine+glioma&recr=Open&rank=13

External Beam Radiation Therapy and Cetuximab Followed by Irinotecan and Cetuximab for Children and Young Adults With Newly Diagnosed Diffuse Pontine Tumors and High-Grade Astrocytomas

Phase
Eligible age-
Study Chair-
Location-
http://clinicaltrial.gov/ct2/show/NCT01012609?term=pontine+glioma&recr=Open&rank=15

Valproic Acid and Radiation Followed by Maintenance Valproic Acid and Bevacizumab in Children With High Grade Gliomas 
Phase 2
Eligible age- 3-21 years
Study Chair- Ira Dunkel
Location- POETIC study- several locations
http://clinicaltrial.gov/ct2/show/NCT00879437?term=brainstem+glioma&recr=Open&rank=9

 Not Yet Open-

Imiquimod/Brain Tumor Initiating Cell (BTIC) Vaccine in Brain Glioma 

Phase 1
Eligible age- 3 to 25 years
Study Chair- Christopher Moetel
Location- Minneapolis. MN
http://clinicaltrial.gov/ct2/show/NCT01400672?term=pontine+glioma&recr=Open&rank=6

DIPG - Current Status and Future Strategies

The September 27^th issue of journal Child’s Nervous System included a review article evaluating where we are with the treatment and research of diffuse intrinsic pontine gliomas.  These authors performed an extensive literature review particularly looking at clinical trials, evolving molecular biology and new therapeutics.

 In their review they found-

• Radiation is the only treatment that has consistently shown clinical and radiographic improvement.  Approximately 70% of the children receiving radiation will have clinical improvement and 30-70% will have radiographic improvement.
• Multiple studies using a combination of radiation and another agent with generally unimpressive results.  Such agents have included RMP-7/carboplatin, topetecan/cisplatin, tamoxifen,  vincristine/vp-16, cisplatin, temozolomide,  vandetanib, and tipifarnib.  However, the vandetanib study showed that those patients that had a higher plasma VEGF level to start had a longer progression free survival whereas those patients that has increasing levels of VEGF with treatment had a shorter progression free survival. (Original vandetanib study- http://www.ncbi.nlm.nih.gov/pubmed/20921456 )
• “No single chemotherapeutic agent alone or in combination, either in a neoadjuvant oradjuvant setting, has proven to increase disease-free survival or alter overall survival in these children with primary or progressive disease.”  This has included avastin and irinotecan which has had some success in adults. 

The prognosis has remained dismal for more than two decades.   This ‘virtual standstill’ for improved prognosis is leveled at:

•  The lack of biologic knowledge about these tumors.
•  Assumptions that adult and pediatric high grade gliomas are the same.
•  The poor drug access to the tumor because of the blood brain barrier.  
•  The lack of experimental models.

Recommendations included:

1. A shift in treatment paradigm to include a diagnostic biopsy to “identify key molecules of unique signaling pathways which could provide clues to potential targets.
2. Development of preclinical (i.e., mouse) models.
3.  “The need to design phase I study with routine sampling along with CED of therapeutic agents is imperative in these fatal tumors.”
4. “Further exploration of these different imaging modalities needs to be continued, and should facilitate better understanding of tumor architecture and metabolic profile as well as to provide more accurate prediction of extent and duration of response following radiation and adjuvant  therapies.”
5. Evaluation of immunotherapy, gene therapy and other innovative techniques.

Diffuse intrinsic pontine glioma-current status and future strategies.

Childs Nerv Syst. 2011 Sep;27(9):1391-7. Epub 2011 Apr 30.
http://www.ncbi.nlm.nih.gov/pubmed/21533575