HKI-272 for HER2-Positive Breast Cancer and Brain Metastases

['lizbeth]

Another option for brain mets - thank heavens, lets hope its a good one!


ClinicalTrials.gov Identifier:
NCT01494662
Purpose

The purpose of this research study is to determine how well neratinib works in treating breast cancer that has spread to the brain. Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2).
In this research study, the investigators are looking to see how well neratinib works to decrease the size of or stabilize breast cancer that has spread to the brain. The investigators are also looking at how previous treatments have affected your thinking (or cognition) and how much neratinib reaches the central nervous system.


http://www.clinicaltrials.gov/ct2/sh...stasis&rank=11

[janice]

Great! maybe I'll check it out. we need hope.

-janice
multiple brain mets 8/15/13, just completed WBR

['lizbeth]

Great, cause I posted the clinical trials with you in mind Janice.

[A. L. Pendley]

I'm interested in the HKI 272 Naratinib + Xeloda + Herceptin trial. I am currently in the Arry 380 trial which has a similar goal - to treat mets in the brain as well as in the rest of the system. I've been in the Arry 380 study now for 5 weeks and get my 6-week scans next week to see if I'm still included in the study (if I'm stable or improved). I want to stay on it, but if I can't, I hope Naratinib becomes another option. I'll be watching what others say on both of these trials! Ann

['lizbeth]

A.L.P.

Please keep us posted on your scans. Wishing you improvement - after all these treatments are supposed to cure us, not fail us!

[donocco]

I did research on HKI-272 and learned a lot. Ill have to reread the articles as it is very complicated. It involves understanding the dynamics of the Her1 and Her2 receptors.

HKI-272 blocks the epidermal growth factor receptor and the Her2Neu receptor. Also the Her4 receptor but I dont know the exact significance of this. In many ways it is like Lapatanib. It blocks EGFR, it blocks the Her2Neu receptor and it gets into the brain. Like Lapatanib it causes definite diarrhea in a fairly large percentage of those taking it. Nerotinib also causes nausea, vomiting,
fatigue and appetite loss. The clinical studies with the drug are just starting so there isnt too much info yet.
The dosage probably will be 240mg daily and the Maximum Tolerated Dose is about 320mg daily. The dose limiting side effect is diarrhea.

So far its exactly like Lapatanib. Yet there is a big difference between the drugs. This is where the chemistry comes in and makes the situation complicated.
Simply put, Nerotinib binds much more strongly to the active site of the HER1 or Her2 (the ATP binding pocket)
than Lapatanib does. Nerotonib forms a strong, permanent covalent bond (this is chemistry of course) where Lapatanib forms much weaker Hydrogen bonds.
Therefore Nerotinib should act more strongly.

The problem with the Her1 and Her2 receptors is that they mutate and once they mutate, Lapatanib doesnt really work anymore. Because of the stronger chemical bond that Nerotinib forms, it is hoped it will be effective in those mutated situations where Lapatanib is not.

There is one mutation in the Her1 and Her2 receptor that is particularly troublesome. It is called the T790 mutation. Once this T790 mutation occurs Lapatanib loses its effectiveness. Hopefully Nerotinib wont because of the stronger chemical bond.

Paul

['lizbeth]

Paul,

Thanks for explaining about HKI-272. I found the chemistry interesting.

This will be one to watch - I'm hoping that it will be more effective for brain mets.

[Rolepaul]

Please continue to ask about Intrathecal Herceptin and IT Pertuzumab for brain and spine mets. All I can say is that the ongoing work in this area is remarkable. Read the input from Marvass and myself. It should give you information you can take to your doctor.
Rolepaul

[dchips1]

Do you know who is doing IT perjeta ? For reference for oncologist. How much IT topotecan dose with Herceptin IT? If topotecan is tolerable Thru Omaya that may be the quickest drug to get approved, and get rid of this stubborn one!

[donocco]

I looked up the dosage of intathecal Topotecan. The Maximum tolerated dose was 0.4mg and itwas given twice a week for 4 weeks. This was an experiental study. Im not sure if its FDA approved. The side effects were headache, nausea and vomiting and back pain. This was seen at a dosage of 0.7mg twice a week. The earlier dosage 0.4mg was decided as the maximum tolerated dose. Hope this helps a bit.

Paul

[DBaroch]

Is anyone in this group in this study or consulting about about participating in this study.