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

Prados Predicted Paradigm Shift for DIPG (diffuse intrinsic pontine glioma)

Three years ago, Dr. Michael Prados was interviewed by Accelerated Brain Cancer Cure on his thoughts of advancements coming for pediatric brain tumors.   Dr Prados immediately focused on the paradigm shift occurring in the medical community to develop unique strategies to fight DIPG though analysis of individual biopsy samples predicting things may change quickly for DIPG.

Why did that paradigm shift occur in the prior year?  Well, French physicians published in the Journal of Neurosurgery 4 years of biopsy results for diffuse pontine lesions.  All 24 children survived the procedure and only 2 suffered some sequela from the intervention developing transient cranial nerve palsies.   One of the two has a worsening of a previous hemiparesis.   Two children had their treatment plan altered because of the biopsy results.

Stereotactic biopsy of diffuse pontine lesions in children

http://www.ncbi.nlm.nih.gov/pubmed/17647306

Neurosurgeon Stefanie Puget has come to North America several times to discuss there ongoing work.   It appears she was just at the Bethesda Consensus Conference earlier this month.

However, it seems that events have moved beyond the discussion stage.   The new multi-institution, 4-armed molecular stratification study is listed as open on clinicaltrials.gov opening first at Dana Farber Boston.   The other institutions slated to collaborate in this trial include -

• University of California, San Francisco
• Children's Hospital Boston
• Children's Memorial Hospital
• Children's Hospital Los Angeles
• University of Utah
• Memorial Sloan-Kettering Cancer Center
• Seattle Children's Hospital
• The Children's Hospital, Denver
• Doernbecher Children's Hospital
• Washington University Children's Hospital
• Miami Children's Hospital
• Johns Hopkins University
• University of Florida
• Children's Hospitals and Clinics of Minnesota
• Southwestern Regional Medical Center
• New York University
• University of Rochester
• University of Mississippi Medical Center
• Louisville Children's Hospital
• Children's Healthcare of Atlanta

http://clinicaltrials.gov/ct2/show/NCT01182350?term=pontine+glioma&rank=4

Accelerate Brain Cancer Cure (ABC²) is a U.S. brain tumor foundation started in 2001 by Dan and Steve Case with the mission to accelerate a cure for brain cancer by increasing the number of potential therapies and moving them rapidly into the clinic for patients.  Since inception,  ABC²  has raised more than 16 million dollars investing in each stage of the development pipeline in pushing for a cure.   It is worth taking a look at the diversity of funding they have engaged in striving for a cure.
http://www.abc2.org/smarter-research

PBTC Phase 2 Study Results for Temozolomide/06-Benzylguanine

An abstract was released ahead of print for a phase 2 Pediatric Brain  Tumor Consortium study on recurrent/progressive high-grade gliomas and brainstem gliomas utilizing the combination of temozolomide and 06-benzylguanine (06 BG).  The study was initially put up on clinicaltrials.gov in January 2006.

O6-Benzylguanine and Temozolomide in Treating Young Patients With Recurrent or Progressive Gliomas or Brain Stem Tumors

http://clinicaltrial.gov/ct2/show/NCT00275002?term=06+temozolomide&rank=10

The thought was that the two agents may work differently to stop tumor growth and that combined chemotherapy might kill more cells.   Temozolomide is an alkylating agent that interferes with DNA replication.  This mechanism of action has seemed dependant on the ability to methylate DNA primarily at the N7 of 0-6 position on guanine.  Some cells were found to be able to repair this DNA damage.  The hope that O6 BG might overcome some of that repair issue.

Of the 41 children evaluated, 16 had brainstem gliomas.  There were no sustained objective responses with any in the brainstem glioma group, however, one patient had long term stable disease of more than 6 courses (28 day course). 

It was concluded that this combination “did not achieve target response rate for pediatric patients with recurrent or progressive high grade glioma or brainstem glioma.”

A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study   
http://www.ncbi.nlm.nih.gov/pubmed/21968943