Sunday, July 26, 2015

For Mat: CDK4/6 inhibitors, PLX8394, or copper chelation?????

Thought about you all day my friend.  Between planting 9 million iris bulbs and repairing a brick wall (mortar mix is an amazing desiccant from which my hands may never recover) at my daughter's "new" house, while shouting curse words (in my head) on your behalf, that even my most tolerant blog audience may find cringe worthy...this is what I (and a brain far better than mine) came up with:

For those unaware of Amazing Mat...I am thinking of a CURE for someone already experienced in BRAF/MEK, ipi, and Keytruda with a brain met near the optic nerve.

Here goes: 

CDK4/6 inhibitors:  
90% of melanoma patients are positive for CDK4/6.
The inhibitor has been proven to cross the blood brain barrier.
Sosman at Vanderbilt has been working with this under the name of LEE011 for some time.
Clinical Trial - NCT01777776: LEE011 and LGX818  is noted to be "active, but not recruiting".
Check out this post from ASCO 2015 (second abstract) where one version (P1446A-05 [voruciclib]) is combined with vermurafenib:  ASCO 2015 new BRAF inhibitor combos
Several other trials with the drug are also noted to be "suspended".  On researching them, the suspension does not appear to be due to patient problems, rather they are due to decisions made by BIG Pharma.
Another CDK4/6 inhibitor:  Palbociclib (PD-0332991) demonstrated "stability" in 27% of patients with melanoma and other cancers.  In another study, a partial response was found in 1 of 31 patients and stability in 29%.
When LEE011 and Binimetinib were combined:  Folks with NRAS mutant melanoma (which may be precluded by your BRAF + status, Mat....but you never know) demonstrated a partial response of 43% as well as stable disease in 43%....per report in Jan 2015.
It's a long shot....but I would call Sosman.  What the heck?  All he can say is no.

A more effective, new generation, BRAF inhibitor - PLX8394?!!!
PLX8394  treats wild and mutated BRAF status melanoma.
May be more effective in BRAF mutated tumors not responsive to other BRAF inhibitors.
Clinical trial #:  NCT02428712 - A study of PLX8394
You have to be refractory to BRAF/MEK, ipi and/or pembro (CHECK!!!).
Do have to have stable brain mets for one month, but sounds pretty flexible and can even be stable on prednisone.
Currently recruiting in Texas, Michigan, Arizona and Utah.

Copper chelation:
Apparently copper is an important co-factor for BRAF mutant melanoma and there is some animal evidence that reducing body levels of copper may inhibit melanoma cells.  Copper chelation for BRAF mutated disease
What's the easiest way to do this?  Duke has been looking at this with an already available drug used to treat copper overload:  Trietine combined with vemurafenib.   Copper starvation could be a promising treatment for some cancers
Clinical trial #:  NCT02068079  Copper chelation and Duke Study
Unfortunately, this study is also "active, but not recruiting".
I would still call.   But, I'm like that.

Much love and warm wishes.  Still thinking. - c

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