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Friday, March 29, 2013

Results of St Jude Phase 1 Trial Published

The results of the St Jude Phase 1 trial using a combination of small molecule inhibitors, vandetanib and dasatinib,  have just been published electronically (ahead of print) in the journal Clinical Cancer Research.

In a look back at DIPG history, this is a really a new kind of trial.   In the past many trials have been radiation and a single agent.  I think we can say with some certainty that DIPG tumors will need more than a single agent for cure- especially for targeted therapies.  These tumors are complex and have so many pathways that it is likely that the tumors will be able to get around a single agent.

In addition, there seems to be rational basis to chose these agents specifically for DIPG.  Vandetanib has a combination of effects on different targets but is a potent VEGF inhibitor.   This is known to be a player in GBMs (and as been said here before when studied histologically most DIPGs have been found to be GBMs).   Dasatinib has its effects at PDGFRA (platelet derived growth factor receptor alpha).  Several recent publications have highlighted the PDGF pathway as being key in the development of DIPGs.

In this study, 25 newly diagnosed children were started on oral dasatinib daily at the start of radiation.   Eight days later oral vandetanib twice a day was added.     Overall the treatment was tolerated well.

  • The M:F ratio was 12:13.
  • The age range was 2.3 years to 17.2 with a median age of 5.8 years.
  • The median treatment time was 184 days.   
  • The most significant toxicity was diarrhea.
  • Myelosuppresion (drop in blood counts) was seen in three children.
  • Two of the children had tumor biospies.  
  • There were 12 post mortem tumor donations.  
  • All patients progressed on treatment.   
  • The one year overall survival was 52% + 10%.
  • The 2 year survival was 9% + 6%.  
  • The two patient who were on treatment for more than 2 years had typical clinical and radiologic appearance of DIPG
An interesting part buried in the article text was the approach to radiation.  The radiation field encompassed the tumor and a 2cm margin in the transverse (across) and caudal (down) direction and a 3cm margin in the superior direction.  The increased from 2cm to 3cm in the superior direction was based on preliminary results on progression patterns of DIPG patients.   Of note, one patient had extensive bilateral thalamic extension requiring whole brain radiation.

Three of the young children developed symptomatic radiation necrosis in uninvolved brain areas.  Although there was no institutional knowledge of other patients treated with more than standard radiation fields developing radiation necrosis in uninvolved areas, it was felt that the larger margins may have lead to symptomatic radiation necrosis.   Thus the authors do not recommend to use of enlarged radiation fields.

Another interesting finding was that the researchers showed "for the first time that CSF exposure of vandetanib and dasatinib in humans is modest".   They point out that CSF levels is often used as a surrogate marker for brain penetration but that this assumption is not necessarily valid particularly in places where there is a blood brain barrier disruption.  They also point out that although the dasatinib CSF level was low that it did reach sustained levels "similar to those causing significant inhibition of other drug targets.

Additionally, the researchers looked at plasma angiogenic factors (seeing what factors are in the blood). Surprisingly, increased VEGF in this study was associated with longer overall survival whereas in a prior study it was associated with shorter survival.  The hypothesis is that this might be because of an improved inhibition of alternative pathways because of the combination.  Regardless of the reason, it seems to me that we don't understand plasma factor levels yet.

Despite the continued poor results for DIPG clinical trials, there were some interesting findings in this trial.   There is hope the drug testing (such as what we should see with the pre-clinical consortium) might find new promising targets or drug therapies.

This work was supported by the U.S. National Institutes of Health Cancer Center
Support (CORE) Grant P30 CA21765, by the Cure Starts Now Foundation, by
AstraZeneca, and by the American Lebanese Syrian Associated Charities (ASLAC).

Phase 1 Trial, Pharmacokinetics and Pharmacodynamics of Vandertanib and Dasatinib in Children with Newly Diagnosed Intrinsic Pontine Gliomas
 2013 Mar 27. [Epub ahead of print]

Clinical Trials Entry