I am so sorry to hear Lynn is not responding well to treatment. I often worry about the day when Andrea’s treatment no longer works. I can’t imagine how difficult this is for you.
I keep a collection of thoughts and ideas for that time, and hopefully they help you. There might be some more localized treatments you can consider, but if it needs a systemic approach, here are things I am thinking about that you might research and talk to the oncologist about:
Losartan is a drug that lowers blood pressure. I mention it first because it is something you could consider right now. It has been prescribed to millions of people, and has a good tolerance profile.
Here is an overview of the research:
http://www.cancerresearchuk.org/about-u … py-in-mice
Here is the main research article:
http://www.nature.com/ncomms/2013/13100 … s3516.html
Why am I interested in this? During the stakeholders meeting, Christine Ferrone from MGH gave a lecture that claimed cholangiocarcinoma defends itself from the immune system by creating a barrier at the cell level. The research paper indicates that Losartan seems to work by lowering cell collagen, increasing the ability of blood to penetrate, and ultimately allowing more chemo to be delivered. They looked at pancreatic (which many have argued is similar to cholangio) and breast cancer cell lines in mice and noticed that the combination of losartan and chemo held the cancer in check much longer. The results are mostly summarized in Figure 7 panel c and panel f for the pancreatic cell line. For the pancreatic cell line, the chemotherapy they used in conjunction with Losartan was 5-FU (a component of FOLFOX). I believe the article argues that Losartan can help chemo work again after the cancer stops reacting. In any event, it has been shown to work in conjunction with a chemotherapy that Lynn is using, and has a reasonable tolerance profile, so based on that I think it is worth bringing up to your oncologist.
While you are waiting to see how FOLFOX does, I would definitely start looking into clinical trials. Immunotherapy seems like a good place to look, especially if cholangio really does have an existing good immune response. You already have identified the NIH trial (NCT01174121). The other hot thing in immunotherapy right now seems to be PD-1 based trials. There have been great results with other cancers for this type of drug, and reason to suspect it could work with cholangiocarcinoma given the immune response. Merck is the furthest along with this drug, and the Merck drug got designated a “breakthrough” drug in March. People seem to expect approval for the Merck drug (pembrolizumab aka lambrolizumab aka mk3475) later this year. If it gets approved soon, you could try to use it off label. If not, you could see if Lynn qualifies for a trial (e.g. NCT02054806). Other companies are coming out with their own anti pd-1 and anti pd-L1 drugs, so I would search for other trials. My rudimentary understanding is the tumors use PD-L1 to “turn off” nearby white blood cells and evade detection/destruction. By suppressing PD-L1 in the body, your immune system is better able to find and kill the cancer.
Since she was on the MET trial, I assume Lynn has gotten a genetic sequencing done on her tumor? If not, I would definitely recommend getting it done. There are a number of trials open based on having a particular genetic mutation (e.g. IDH, KRAS, MET, NOTCH, + lots more). One I am focusing on is the IDH1/IDH2 mutation. A trial was opened up in March for intrahepatic cholangiocarcinoma patients that have the IDH1 mutation:
The odds seem pretty decent for having this mutation. If I recall correctly, the company running the trial (Agios), estimates that 20% of ICC patients carry the IDH1 mutation. An earlier paper by Foundation Medicine indicated that IDH1/IDH2 was found in ~35% of cholangiocarcinoma patients (If you have survived a while with ICC, the odds may even be a little better of having IDH1 since this mutation seems to be associated with above average survival in other cancers). The company had very good results with its initial trial of an IDH2 blocker and blood cancers. The scientists seem to be pretty excited about IDH1/IDH2 blockers and cholangiocarcinoma, so that seems like one to look at. For IDH1, my rudimentary understanding here is that cells with this mutation create IDH1 concentrations which causes immature cells to stop maturing and instead replicate (thus becoming cancerous). By suppressing IDH1, the immature cells stop prematurely multiplying, and continue to develop into normal cells.
One thing I truly believe is that if you want a different result, you are going to have to do something different. That is why I am a big fan of doing as many clinical trials as needed/possible to find something that works. Hopefully, some of these ideas help.
My heart goes out to you and Lynn,
PS - I think irinotecan is a common second line chemotherapy for cholangio. Since Lynn is using FOLFOX rather than FOLFIRINOX, I assume she is not taking irinotecan? Is there a reason for that?