XL518 drug testing

crazylady

Hi Everyone,

I was wondering if anyone had any information on XL518. I may be eligible to participate in a study and am trying to gather as much information as possible before I make a final decision.

Thank You,
Jamie

Trapbear

XL518

This is a MEK inhibitor, MEK is involved in signal transduction which ultimately causes a cell to divide. Cancer is basically cells that keep dividing, growing unchecked. Preclinically this drug worked best on tumors with muations in B-RAF. This mutation is not very common in colon cancer (about 10%). About 43% of colon cancer pts have K-RAS mutations (and do not respond to Erbitux). RAS is in the same pathway. I think researchers are not sure how genotype affects response to MEK inhibitors so they will probably test in all comers and do genotyping. I am a cancer researcher and used to work at Genentech. Below is some more information on the MEK inhibitor. Good luck.
Bill


MEK inhibitor XL518
An orally active small molecule, targeting mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), with potential antineoplastic activity. MEK inhibitor XL518 specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a B-RAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

flash g

Trapbear said:

XL518

This is a MEK inhibitor, MEK is involved in signal transduction which ultimately causes a cell to divide. Cancer is basically cells that keep dividing, growing unchecked. Preclinically this drug worked best on tumors with muations in B-RAF. This mutation is not very common in colon cancer (about 10%). About 43% of colon cancer pts have K-RAS mutations (and do not respond to Erbitux). RAS is in the same pathway. I think researchers are not sure how genotype affects response to MEK inhibitors so they will probably test in all comers and do genotyping. I am a cancer researcher and used to work at Genentech. Below is some more information on the MEK inhibitor. Good luck.
Bill


MEK inhibitor XL518
An orally active small molecule, targeting mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), with potential antineoplastic activity. MEK inhibitor XL518 specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a B-RAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

HIFU (high intensity focused ultrasound)
Hi Trap Bear,
I note you are a Cancer researcher. Have you any information regarding HIFU and rectal cancer? I have to decide between the usual chem/RT and surgery. HIFU may be an alternate route but ita not approved or practiced in western meds. Any info welcomed. FG

Trapbear

flash g said:

HIFU (high intensity focused ultrasound)
Hi Trap Bear,
I note you are a Cancer researcher. Have you any information regarding HIFU and rectal cancer? I have to decide between the usual chem/RT and surgery. HIFU may be an alternate route but ita not approved or practiced in western meds. Any info welcomed. FG

HI Flash G
Sorry, don't have any experience with HIFU.

jscho

Trapbear said:

XL518

This is a MEK inhibitor, MEK is involved in signal transduction which ultimately causes a cell to divide. Cancer is basically cells that keep dividing, growing unchecked. Preclinically this drug worked best on tumors with muations in B-RAF. This mutation is not very common in colon cancer (about 10%). About 43% of colon cancer pts have K-RAS mutations (and do not respond to Erbitux). RAS is in the same pathway. I think researchers are not sure how genotype affects response to MEK inhibitors so they will probably test in all comers and do genotyping. I am a cancer researcher and used to work at Genentech. Below is some more information on the MEK inhibitor. Good luck.
Bill


MEK inhibitor XL518
An orally active small molecule, targeting mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), with potential antineoplastic activity. MEK inhibitor XL518 specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a B-RAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

why mutated braf?
Trapbear, can you provide a rationale behind why mutated B-RAF should respond better to MEK inhibitors? It seems to me that since MEK is downstream of RAF, MEK inhibitors should affect all upstream pathways regardless of mutational status, including VEGF, c-KIT, FLT-3, PDGF and EGF signals. Is it simply because a constitutively active RAF is shut down most effectively, whereas cross-talk can allow proliferation of other signals? I would think that mutated RAS would also respond well, since it is not far removed from MEK.

I find the science of cancer research fascinating, though the day-to-day existence of a researcher probably isn't too exciting.

Best,
Jeremy

Trapbear

jscho said:

why mutated braf?
Trapbear, can you provide a rationale behind why mutated B-RAF should respond better to MEK inhibitors? It seems to me that since MEK is downstream of RAF, MEK inhibitors should affect all upstream pathways regardless of mutational status, including VEGF, c-KIT, FLT-3, PDGF and EGF signals. Is it simply because a constitutively active RAF is shut down most effectively, whereas cross-talk can allow proliferation of other signals? I would think that mutated RAS would also respond well, since it is not far removed from MEK.

I find the science of cancer research fascinating, though the day-to-day existence of a researcher probably isn't too exciting.

Best,
Jeremy

You can do a lot of
You can do a lot of hand-waving to make many hypotheses for why a B-RAF mutant cell responds better to a MEK inhibitor (since it is downstream) I think the most popular hypothesis is that BRAF mutant cells are addicted to this pathway for their growth, so inhibiting any enzyme along this pathway will cause the cell to die. Unfortunatley, most tumors eventually develop mutations in other pathways that allow them to grow in the presence of a MEK inhibitor. This is the reason it is best to use a cocktail that can inhibit many pathways at the same time. This is what revolutionized HIV treatment, which is now a very manageable chronic disease. Let's hope we can do the same for cancer.

crazylady

Trapbear said:

You can do a lot of
You can do a lot of hand-waving to make many hypotheses for why a B-RAF mutant cell responds better to a MEK inhibitor (since it is downstream) I think the most popular hypothesis is that BRAF mutant cells are addicted to this pathway for their growth, so inhibiting any enzyme along this pathway will cause the cell to die. Unfortunatley, most tumors eventually develop mutations in other pathways that allow them to grow in the presence of a MEK inhibitor. This is the reason it is best to use a cocktail that can inhibit many pathways at the same time. This is what revolutionized HIV treatment, which is now a very manageable chronic disease. Let's hope we can do the same for cancer.

Thank You
Trapbear, thank you for the information. Do you know anything about how effective this drug has been in Phase 1 trials. I have run out of chemo options, but am not sure that I'm ready to go with a drug trial. Of course, there don't seem to be any other options at this point. I do have the K-ras mutation.
As a cancer researcher what is your take on the drug trial?

Trapbear

crazylady said:

Thank You
Trapbear, thank you for the information. Do you know anything about how effective this drug has been in Phase 1 trials. I have run out of chemo options, but am not sure that I'm ready to go with a drug trial. Of course, there don't seem to be any other options at this point. I do have the K-ras mutation.
As a cancer researcher what is your take on the drug trial?

Phase I data
Here is a link to the results of the Phase I trial presented last June.
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=35980
Remember, Phase I trials only look at safety and pharmacokinetics. Efficacy is not an endpoint until Phase II, and these trials will need a placebo control. The results from the Phase I suggest that it is safe, well tolerated, and there was some evidence of biological activity in pts (those are the PD endpoints they discuss). The who raf/ras pathway is important in colon cancer so it might be worth a try? The fact that you are KRAS mutant suggests that this pathway is a driver of your disease. I heard that they are still recruiting for a Phase Ib trial where they will combine the MEK inhibitor with a PI3K inhibitor. I would go for this one if you could. This targets two pathways, both of which are important in RAS mutant pts. Sorry I can't be of more help, hang in there, this is a marathon.....My husband just started folfiri plus avastin this week, he has recurrence in his lungs.
Take care,

Trapbear

Trapbear said:

Phase I data
Here is a link to the results of the Phase I trial presented last June.
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=35980
Remember, Phase I trials only look at safety and pharmacokinetics. Efficacy is not an endpoint until Phase II, and these trials will need a placebo control. The results from the Phase I suggest that it is safe, well tolerated, and there was some evidence of biological activity in pts (those are the PD endpoints they discuss). The who raf/ras pathway is important in colon cancer so it might be worth a try? The fact that you are KRAS mutant suggests that this pathway is a driver of your disease. I heard that they are still recruiting for a Phase Ib trial where they will combine the MEK inhibitor with a PI3K inhibitor. I would go for this one if you could. This targets two pathways, both of which are important in RAS mutant pts. Sorry I can't be of more help, hang in there, this is a marathon.....My husband just started folfiri plus avastin this week, he has recurrence in his lungs.
Take care,

Phase Ib trial sites
Jaime,
They are running this trial at Dana Farber (Boston), Sarah Cannon (Nashville), and Karmanos (Detroit)
Good Luck

robinvan

Trapbear said:

Phase I data
Here is a link to the results of the Phase I trial presented last June.
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=35980
Remember, Phase I trials only look at safety and pharmacokinetics. Efficacy is not an endpoint until Phase II, and these trials will need a placebo control. The results from the Phase I suggest that it is safe, well tolerated, and there was some evidence of biological activity in pts (those are the PD endpoints they discuss). The who raf/ras pathway is important in colon cancer so it might be worth a try? The fact that you are KRAS mutant suggests that this pathway is a driver of your disease. I heard that they are still recruiting for a Phase Ib trial where they will combine the MEK inhibitor with a PI3K inhibitor. I would go for this one if you could. This targets two pathways, both of which are important in RAS mutant pts. Sorry I can't be of more help, hang in there, this is a marathon.....My husband just started folfiri plus avastin this week, he has recurrence in his lungs.
Take care,

Sorry to hear about recurrences
Trapbear,
I know how he feels. I'm dealing with recurrence #2. My first was liver. RFA and xeloda, irinotecan, avastin cleared it up nicely. Know it is sacrum. Radiation/Erbitux seems to be working well. I hope he has good success.

Jamie,
I hope you find something to work with.

Rob; in Vancouver

"Sometimes you have to fight a battle more than once to win" Maggie T.

Trapbear

robinvan said:

Sorry to hear about recurrences
Trapbear,
I know how he feels. I'm dealing with recurrence #2. My first was liver. RFA and xeloda, irinotecan, avastin cleared it up nicely. Know it is sacrum. Radiation/Erbitux seems to be working well. I hope he has good success.

Jamie,
I hope you find something to work with.

Rob; in Vancouver

"Sometimes you have to fight a battle more than once to win" Maggie T.

Thanks Rob
Thanks Rob, we are hopeful that the irinotecan and avastin do their stuff and zap the lung nodules. They are still small, about 1cm, but too many to allow surgery or RFA, at least what the onc says now. He is KRAS mutant, so no Erbitux.
Take care,

crazylady

Trapbear said:

Phase Ib trial sites
Jaime,
They are running this trial at Dana Farber (Boston), Sarah Cannon (Nashville), and Karmanos (Detroit)
Good Luck

Phase 2
Thank You Trapbear,
I am being offered a phase 2 trial and have been told that there will be no placebo. I will find out more information on Monday.

I hope your husband does well on chemo. I am also dealing with small lung mets that are inoperable due to one being too close to my heart.

Take care,
Jamie

crazylady

robinvan said:

Sorry to hear about recurrences
Trapbear,
I know how he feels. I'm dealing with recurrence #2. My first was liver. RFA and xeloda, irinotecan, avastin cleared it up nicely. Know it is sacrum. Radiation/Erbitux seems to be working well. I hope he has good success.

Jamie,
I hope you find something to work with.

Rob; in Vancouver

"Sometimes you have to fight a battle more than once to win" Maggie T.

Hi Rob
Hi Rob,

Good to hear from you. I'm glad the radiation/erbitux combo seems to be working well.
Take care and have a good weekend!
Jamie