Netherlands Radiolabeled Bevacizumab Trial

In the age of molecularly-targeted chemotherapy, diffuse intrinsic pontine gliomas are tough tumors.  DIPGs seem to be molecularly heterogenous tumors- not only between individuals but also within a single tumor.  If one can not obtain tissue then it is impossible to know if a particular tumor even has the target.  And if one does get a biopsy the concern is is really representative?

There is also the concern perhaps the brainstem is more difficult to get agents in- is the blood brain barrier just more tight in that area?

For me the question has been, how do we address these concerns clinically?  It appear that the researchers at VU University Medical Center in the Netherlands are trying to look at these questions by using an immuno-PET approach.

Immuno-PET scanning  uses a radio-labeled monoclonoal antibody.   The idea is that the radio-labeled agent will stick at the place where there is the specific receptor and the tag will let it light up on the scan.   One could think of it as "a comprehensive immunohistochemical stain in vivo".    In this case the monoclonal antibody bevacizumab is labeled with 89Zr.  PET scans will be done at 1, 72 and 144 hours after administration.

Immuno-PET looks like a  novel way to get answers to some of these questions.  My hope is that this study will provide new knowledge on drug distribution with a anti-VEGF in DIPG.   Since pediatric high grade gliomas are also included it will be interesting to compare these two different populations.

This research has been supported by Stichting Semmy.

Reference:
Determining the tumor uptake of labelled bevacizumab in children with high grade or diffuse intrinsic pontine glioma on PET Scans
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3518

Immuno-PET: a navigator in monoclonal antibody development and applications.
Full Text-http://theoncologist.alphamedpress.org/content/12/12/1379.long

Patterns of Progression in Pediatric Patients with High-Grade Glioma or Diffuse Intrinsic Pontine Glioma treated with Bevacizumab-Based Therapy at Diagnosis

The first hints of data from a Cincinnati/Lurie Children's study using temozolomide, irinotecan and avastin appears to be coming out with a poster presentation at the 3rd biennial Pediatric Basic and Translational Research Conference looking at patterns of progression with an avastin-based therapy for kids with newly diagnosed DIPG or high grade glioma.

The issues of potential increased invasiveness and spread have been popping up for the past few years. We have seen discussions of this in internet-based communities as well as publications in adult GBM patients.   Common terms related to this are "diffuse invasiveness" and "evasive resistance".   The adult literature has some that do not believe that avastin increases remote relapses.  There is very little regarding children relapse patterns with bevacizumab-based therapies.

In this study of 17 patients (14 DIPG and 3 HGG), 12 patients had progressive disease in a median time of 8.2 months.  In nine patients the furst progression was local and  in the remaining three the progression was local, diffuse and distant.   However with further progressive disease a total of six children had diffuse or distant progression.

The authors speculate that these findings might be explained by increasing invasiveness through co-opting native blood vessels or activation of other pro-angiogenic pathways.     

It would be interesting to have direct comparison to non-bevacizamab-based therapies for comparison as other authors have indicated a high risk of leptomeningeal dissemination with DIPG.  Interestingly, in that study 8 of the 16 children had leptomeningeal spread but only the 3 with anti-VEGF (2 with avastin and 1 with vandetanib) had spread to bilateral cerebral hemispheres.  The other 5 had spread to the spinal cord or posterior fossa.

It is likely questions like this is where a registry can be valuable if one is able to look at a large number of imaging studies. 

Reference:
Patterns of Progression in Pediatric Patients with High-Grade Glioma or Diffuse Intrinsic Pontine Glioma treated with Bevacizumab-Based Therapy at Diagnosis
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=736163

A Study of Bevacizumab Therapy in Patients With Newly Diagnosed High-Grade Gliomas and Diffuse Intrinsic Pontine Gliomas
http://clinicaltrials.gov/ct2/show/NCT00890786?term=dipg&rank=10

Bevacizumab does not increase remote relapse in malignant glioma
http://www.ncbi.nlm.nih.gov/pubmed/21446027

Prospective neuroaxis surveillance reviews a high risk of leptmeningeal dissemination in diffuse intrinsic pontine glioma.
http://www.ncbi.nlm.nih.gov/pubmed/20623246

Case Report- Two Children with Prolonged Survival

During time period between June 2008 and June 2009, Children’s Healthcare of Atlanta treated three children diagnosed with DIPG with radiation followed by temozolomide and avastin.   Two children were still alive at 37 and 47 months from diagnosis.  The other child had progression free survival for 12 months followed by rapid deterioration with death at 14 months from diagnosis. 

Here is the recent case report of these two children who have surpassed the 3-year mark since diagnosis of a DIPG and were still going strong at the time of publication.

Patient 1- was described as an 11-year-old male with a 2 month history of weakness on the left side as well as walking and swallowing difficulties.   The initial MRI showed a 4cmx3.5cmx3cm non-enhancing tumor of the pons and medulla.  

Patient 2-was described as an asymptomatic 7-year-old female who was found to incidentally have a 3cmx2.3cmx2.6cm pontine mass after head trauma.   She was observed closely with serial MRIs.  Two MRIs showed increased tumor size and at 8 months from initial presentation she deteriorated developing a facial palsy, right sided weakness and hydrocephalus.  The tumor was 4.2cmx4.3x3.8cm with new focal areas of enhancement.

The children were treated with temozolomide 200mg/2d/d for 5 days ever 28 days and avastin 10mg.kg.dose every 14 days.   In both patients a 65% decrease in tumor size was seen.   No steroids were needed after 10 weeks from radiation.   The therapy was tolerated well.  At publication both children were doing well and continuing on treatment.  The paper notes that the boy was going to school and playing soccer at 37 months.  

 (Note- the actual paper has several MRI images provided both initially and later for both children.)

The authors speculate that the combination of temozolomide and avastin might deliver more temozolamide to the tumor because avastin might normalize the tumor vasculature.    As support for this theory the authors point to cilengtide altering perfusion which allowed for increased temozolamide delivery  for gliomas.    Perhaps avastin has a similar effect.

An additional advantage of this combination might be the decreased need for steroids.

The authors recommend consideration of an expanded DIPG clinical trial with this combination.

By the way, the female child appears to be atypical both in presentation and focality in her tumor.   On the other hand, the male child seems to have a very typical presentation for DIPG.

Reference:

Prolonged survival after treatment of diffuse intrinsic pontine glioma with radiation, temozolamide, and bevacizumab: report of 2 cases.

J Pediatr Hematol Oncol. 2013 Jan;35(1):e42-6.

http://www.ncbi.nlm.nih.gov/pubmed/23249962

Avastin

On March 31, 2009 -- this Tuesday -- the FDA will hold an open public hearing to discuss approval of Avastin as a single agent in previously treated glioblastoma multiforme. The hearing will take place from 8:30 a.m. to 4:30 p.m. at the Hilton Washington DC/Silver Spring. Although this hearing is for an adult indication, we believe this matter deserves the attention of the brain tumor community at large. Moreover, we are seeing Aavastin being used with our DIPG kids more and more frequently.

There is some concern in the adult community that a negative review from the FDA will result in insurance companies refusing to pay for Avastin for any brain tumor patient.

Because this is an issue that may very well directly impact the DIPG community specifically, and most certainly will impact the entire brain tumor community, we delivered the following letter in support of Avastin for the Committee's consideration:


ODAC Committee Members:

We, the Board members of Just One More Day, are writing to urge the Committee to recommend approval of Avastin as a single agent in recurrent glioblastoma multiforme.
Just One More Day is a non-profit foundation formed by parents to help other parents whose children have been diagnosed with pediatric diffuse intrinsic pontine gliomas (“DIPG”), a cancerous tumor which invades the brainstem. DIPGs are almost always terminal, with most children dying within one year of diagnosis. In thirty years, and despite multiple different trials, no chemotherapy has been found to be effective against DIPG. With Avastin, however, there is hope.

Although DIPGs are generally considered inoperable, DIPG lesions were biopsied as part of a recent French study. The study revealed that the vast majority of DIPGs are high-grade gliomas, with many being glioblastoma multiforme.

In our network of parents we have seen many of our children with DIPGs stabilize with Avastin. In fact, we have recently been overjoyed by dramatic regression of the DIPG in Andrew, son of one of our Board members, after he received a single cycle of Avastin. Avastin has provided a flicker of hope in the dismal world of diffuse intrinsic pontine gliomas.

We realize that the question before the committee is whether to recommend approval of Avastin as a single agent in recurrent glioblastoma. Unfortunately, the call for written testimony did not indicate whether the question addresses both adults and children or only adults. Regardless, we believe it is important that our voice be heard on the matter. We are directly impacted by what is being done for adults with brain tumors, as treatments are usually not approved for children until they pass through the approval process for adults. Articles such as Antiangiogenic Therapy Using Bevacizumab in Recurrent High-Grade Glioma: Impact on Local Control and Patient Survival (J. Neurosurg. 2009 Jan; l 10(1): 173-80)) are encouraging and reflect what we are seeing with our children.

We ask the committee pause and reflect on the impact of this recommendation to the entire brain tumor community -- including our children. Previously there has been so little hope for children with DIPGs. Even a little more time with our children – even, as our name reflects, just one more day -- is incredibly precious to us. Please help the flame of this hope continue to burn and, we hope, to grow even brighter.

None of our board members have financial conflicts regarding the approval of Avastin.

Thank you for your time and consideration.



Background information is available at-
Meeting background http://www.fda.gov/ohrms/dockets/ac/cder09.html#OncologicDrugs
27 page document from Genetech http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4427b1-01-FDA.pdf