Pediatric Consortium Study

[biopearl]

From the Pediatric Consortium study June 27 2016 published online (will try to post link, if not maybe Fish can help)

<<Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.>> bp

[biopearl]

Reference:Cite this article as:
Salloum, R., Hummel, T.R., Kumar, S.S. et al. J Neurooncol (2016). doi:10.1007/s11060-016-2189-7

[Fishermangents]

Bio, I saw this report also recently. The full title is:
A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study.

link: http://www.ncbi.nlm.nih.gov/pubmed/27350411

Imetelstat did show some effect, but the regimen was too toxic for these patients. It seems to be mainly grade 4 myelosuppression: "Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors." It also states: "Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient." I am not totally sure what it means exactly, but it could refer to some strong activity. I will try to read a bit more about it.

The 'regimen' was too toxic. That may leave the possibility of trying another regimen.

[biopearl]

Hi Fish, sorry I had to post and run, had a lot of work. Have been thinking about this study a bit. It is really very similar in content to the earlier study citing the need to stop enrollment and the findings of enrollment limiting toxicity. At least we know that Imetelstat gets into the tumor (2 patients) and has and a peripheral effect as well. No clinical effect on 40 patients is pretty disheartening. I interpret this to mean that there was no regression, no effect on recurrence no slowing of growth and basically no evidence on tumor behavior at all. As I recall ependymoma cells seemed very responsive in vitro so I was hoping we would see something. The fact that the study continued and allowed drug administration to forty children suggests forty totally hopeless situations in search of some treatment. Not even a glimmer of drug effect on tumors even though it got in. I feel kind of sad about this especially when it comes to kids with hopeless diseases. Perhaps combo therapy (our new mantra). Looks like we will be sticking with hematologic malignancies for a while. bp

[Fishermangents]

Bio, guess you're right.

[huntingonthebluffs]

I do not understand the science or the clinical study process very well. Still, I was wondering if since we are dealing with children in this study, the dosage and frequency appeared very different (assuming due in part to the the toxity, patient size, disease, etc). Could this study then preclude doing a study in adults and in a different manner regarding dosage, frequency with or without the use of combo therapy, etc.? Or even trying a new study for children using other criteria? I understand certain tumors (e.g. brain and lung tumors) can be difficult to treat, so much has to be considered in the application of the drugs. I was wondering if you think this failed study will preclude more happening in this space any time soon? Obviously not all studies are successful but I hope all studies provide data that might lead to other studies and options for others, including these kids. As always, thanks again for your thoughts.

[Fishermangents]

Hunt, I certainly believe that studies that haven't continued (for whatever reason) are an important source of information to JnJ and Geron. This all contributes to getting a better picture of the workings of imetelstat in human biology.

Choices on which disease to target next and how (single vs combo; if combo: which combo?) are complicated. My guess is that they will stay with the hem-oncs for the moment (MF, MDS, AML, maybe MM), as they smell potential success there. Although getting approval certainly is their top priority, I am sure a team of scientist is working on next steps. It is a balancing act between factors such as severenes of the disease, likelyhood that imet will have a positive impact, size of the market (number of patients, competing drugs), how successful is an existing BAT... etc. Very complex and impactful choices to make.

[biopearl]

Hunt, agree with Fish, doubt we will see any solid tumor studies for a while, J and J has their hands full with hematologic diseases. I think it is safe to conclude that clinical solid tumor studies to date have been abject failures. Heck I don't even know if they still plan for the AML study based on the complete absence of information from yesterdays conference call. The former guidance for a second half start to an AML study seems to have evaporated or did I just miss this, Fish what is your take. (I will start a new thread with some thoughts about the conference call.) bp

[Fishermangents]

The AML study has been anounced various times during all the recent calls and meetings where Dr. Scarlet spoke. Apart from this last Q2 call. After so many announcements this can't just evaporate. It would be a major change of plan. We have still a couple of months to go in 2H 2016, so it is too early to draw conlusions. If we haven't heard anything about the AML trial by 1st January 2017, I would start worrying. But I am confident that before that time we will have been updated about the AML trial, whatever it will be.