Are you currently (or have you been) in a Clinical Trial?
I am about to start a clinical trial and am wondering about the experiences of others. I'm feeling a little rocky and at sea, because I've been in the care of a wonderful oncologist for the past three years, and I knew without a doubt that his prime objective was the same as mine - to keep me stable and maintain a good quality of life. It was all about me.
Now, I'm embarking on this trial on a different campus and with a different doctor. I really like the doctor who heads it (he is a close colleague of my oncologist and has conferred with him), but I not-so-secretly worry that the prime focus will not be on my well-being, that it will be secondary to the study objectives. My initial meeting with the CO pretty much dispelled my fear that I would be a lab rat, but the closer I get to starting, the more leery I get. I'm normally not anxious about treatments.
I haven't had any treatment at all for several weeks, because the last treatment was ineffective and my onc wanted to get me into a trial, so the waiting hasn't helped. I'm normally pretty chill about everything, including starting new treatments, but entering a clinical trial is a different kettle of fish.
What has been your experience? Have you felt cared for?
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I am on my fourth clinical trial (I was on 3 concurrently) and I have to say that you get more scans, more appts, more questions about symptoms & how long they last. I think much depends on the trial RN. My last one was a stickler for details, the one I have now is a bit more chill but both of them still great.
I had a very bad time on the new trial & found that they cared less about the outcome of the trial & were willing to read between the lines & make "work arounds" to make the trial work for me instead of me working for the trial.
Having said this, I am in Canada so there may be differences in how things work. I am luckily with my same MO, not the one who is running the trial, so that may make a difference too.
Good luck!
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Thank you, GG27! My initial meetings with the team have been positive, but it's all a new thing with new people in a new place to me, so I'm getting more antsy. I was supposed to complete the screening tests tomorrow, but just got word that they have all been pushed up a week due to an issue with the sponsor, so more toe-tapping and waiting. I was dreading starting it, but now I'm pissed that it's been postponed!
I'm glad to hear that you have a good relationship with your nurse, especially when you were having serious problems. I love your phrase, making the trial work for you rather than you working for the trial; I may be using that in the future!
Have a good week and happy holidays!
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I’ve done 2 trials.
One (a phase 3) went very smooth and the coordinator scheduled all my appointments and made sure everything flowed nicely. She made sure that I was doing ok on treatment and recorded everything. I had great results cancer wise as well.
Second (phase 1) trial was a nightmare. The coordinator didn’t schedule well and always said we could just walk down there and push ourselves in to get a scan or bloodwork done because trial patients have more sway. I didn’t like that at all. She also didn’t seem to take note of my symptoms, although she was a very nice lady. I ended up being pulled from the trial by my MO. This kept me off of any treatment for a few months which is critical for how aggressive triple negative BC is. The coordinator told me people had been reporting skin irritation and a rash. What I ended up getting was what I refer to as the great Chicken Plague of 2018. I had red bumps (size of a chocolate chip) all over my back and shoulders with a few starting to appear on my neck, arms and legs. Although I’ve been off this trial for months these bumps have left scars. I also had mysterious brain edema develop during this trial that we still are trying to fix. The hard part is that the trial was working! Because of that I have been able to push my insurance to approve me just receiving the FDA approved medicine from the trial and that is working in some areas. I can’t say it was a complete bust.
With both trials all my treatments were covered by the trial instead of my insurance. So that is a nice perk.
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Thank you, Sierra, I really appreciate your input. I have been off treatment now since the end of September, which with aggressive liver mets is no bueno. Luckily, I have no pain, no swelling and my liver is chugging along, but I'm not happy with these delays in treatment. I won't know until 12/10 if I will be part of this immunotherapy trial. There is another trial that I might get into, but who knows how long that will take or if I would have to repeat all of the screening tests I will have had by then.
I have a TN friend who also got a horrendous rash all over her body from a clinical trial. They couldn't control it well and told her that she would have lasting scars and maybe blotches?
I hope that the coming months are filled with more plusses than minuses for you!
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The waiting period to get into a trial is scary! I’ve heard that for some you need to be off of your previous treatment for x amount of weeks before they start the vetting process. There is a vaccine trial my MO offered me, but it would take months for them to develop my ‘vaccine’ and we both agreed that’s not something I can afford to do right now. It’s like playing the lottery in a way. You hope you strike it rich, lol.
I hope your trial gets moving along soon enough. Waiting can make you go mad. At the end of the day they (trail coordinators or your MO) should be most concerned about you, your life and QOL. I don’t think you should ever feel like a lab rat or that the data is more important
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I've now been in this immunotherapy trial at for three weeks and will start my second cycle of treatment on 1/8. I get one infusion of Opdivo/Nivolumab on the first day of each cycle (only once per month) followed by 8 hours of hourly blood work and EKGs. That is one L-O-N-G day; the first day of the initial cycle I was at MDA from 8am until 12:30am the next day, due to some delays. I take two oral doses of the test drug daily with a 6 hour fast before the dose and two hour dose afterwards. So far, no SEs (a few minor patches of rash) and my blood work has been good. I am feeling great. Both immunotherapy drugs are hard on the kidneys, so I have to keep pushing myself to drink enough water to stay hydrated and flush my kidneys.
The rigorous schedule of visits and fasting regime around each day's oral meds has taken some adjusting to, but after the first week, I figured out what worked best for me and accepted the rest. Everyone I've come into contact with so far has been wonderful, and I am addicted to being covered with heated blankets on demand. Living the life! Assuming that all continues to go well this month, my next *pass or fail* scan will be in early February.
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Thanks for the update!
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Bumped into this link. It's about new trials added to Metastatic Trial Search in January 2019
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Thanks, Daniel!
Katty
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I had a subcutaneous tumor on my lower left back that had been increasing in size per every scan since this summer. It was very easy to palpate. This is the tumor that was biopsied right before the start of the trial, and I am scheduled for a comparison biopsy on the same area next week. After one month on my clinical trial, it can no longer be felt! It's funny, I noticed the night before my appointment that I couldn't feel anything there, but didn't trust my own fingers or my husband's. I was SO happy that the doc couldn't feel anything, either!
I don't allow myself to get wildly optimistic about anything - I know better - but DAMN!!!
My doc says that's an indication that the immunotherapy treatment should be working to a degree in all other cancerous areas as well (C'MON LIVER!!!), but I won't know to what extent until my scan in February. He was practically dancing a jig!
Sign me,
Cautiously Optimistic Katty
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Oh, such interesting information Katty!
I've had fun reading up on this a bit. I assumed your trial was a standard immunotherapy combination (CTLA-4 and Opodivo) but instead you are taking a new targeted drug (Prostaglandin E receptor inhibitor, EP4, encoded by the PTERG4) plus Nivolumab (checkpoint immunotherapy drug).
Your cancer may over-express EP4, which is turned on by COX2. Interestingly, this is the pathway that controls the pain and inflammation of osteoarthritis, so your knee feeling better may well be a consequence not just of stopping the femara, but also from the analgesic NSAID-like effect of the EP4 inhibitor drug.
Fortuitously, inhibiting this pathway also disrupts the mechanism that cancer cells use to hide from the immune system. Hence the study, to see if these EP4 inhibitor drug allows the cancer to respond to immunotherapy and be killed by your immune system.
I could not find how frequent is this EP4 over-expression, but it is one way that cancer cells escape from the inhibiting effects of anti-estrogens. The cells turn on COX-2, which turns on EP4, and in turn this enables the estrogen receptor to activate cancer growth genes even in the absence of estrogen. A different way you can get progression on I/F therapy is if the cancer mutates the PI3K receptor, or develops ESR1 mutations. Would love to know how common (or rare) it is to get EP4 over-expression.
Good luck on the scans! It will be so exciting if it works! Do you know if you are getting both drugs?
PS It is worth noting that your clinical trial is also offered in AUSTRALIA and SPAIN!
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Yes, I am getting the Full Monty, er, both drugs! I'm going to print out your e-mail and take it to my next meeting with my doc, thank you! I am grateful for your research! Yes, I saw that they will be recruiting in Australia and Spain, wonderful! So far, I am THE only patient enrolled at MDA. As I told my hubby after my good checkup this week, I am the shit!
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No worries, if you are responding to immunotherapy you won't be alone for long!!!
Remind me what are you finding in the way of side effects, so far?!
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Below is some more information from a recent review. The high levels of EP4 are not only promoting metastasis but also directly blocking the ability of the immune system to recognize and kill the cancer, so you get benefit on both fronts from the drug. Sounds like this combo should also work great on triple-negative breast cancers. Please ask the docs if they have had success with other MBC patients? The other point they make here is that the newer COX2 inhibitor drugs are formulated so they won't have the heart problems seen in earlier Celebrex-type drugs. Interesting that your trial is open to all comers, does not require any specific COX2 or EP4 expression levels, just have to have measurable disease...
From the Review (2018):
We make a case for EP4 as a promising newer therapeutic target for treating breast cancer. We show that an aberrant over-expression of cyclooxygenase (COX)-2, which is an inflammation-associated enzyme, occurring in 40–50% of breast cancer patients leads to tumor progression and metastasis due to multiple cellular events resulting from an increased prostaglandin (PG) E2 production in the tumor milieu. They include inactivation of host anti-tumor immune cells, such as Natural Killer (NK) and T cells, increased immuno-suppressor function of tumor-associated macrophages, promotion of tumor cell migration, invasiveness and tumor-associated angiogenesis, due to upregulation of multiple angiogenic factors including Vascular Endothelial Growth Factor (VEGF)-A, increased lymphangiogenesis (due to upregulation of VEGF-C/D), and a stimulation of stem-like cell (SLC) phenotype in cancer cells.
All of these events were primarily mediated by activation of the Prostaglandin (PG) E receptor EP4 on tumor or host cells. We show that selective EP4 antagonists (EP4A) could mitigate all of these events tested with cells in vitro as well as in vivo in syngeneic COX-2 expressing mammary cancer bearing mice or immune-deficient mice bearing COX-2 over-expressing human breast cancer xenografts. We suggest that EP4A can avoid thrombo-embolic side effects of long term use of COX-2 inhibitors by sparing cardio-protective roles of PGI2 via IP receptor activation or PGE2 via EP3 receptor activation. Furthermore, we identified two COX-2/EP4 induced oncogenic and SLC-stimulating microRNAs—miR526b and miR655, one of which (miR655) appears to be a potential blood biomarker in breast cancer patients for monitoring SLC-ablative therapies, such as with EP4A.
We suggest that EP4A will likely produce the highest benefit in aggressive breast cancers, such as COX-2 expressing triple-negative breast cancers, when combined with other newer agents, such as inhibitors of programmed cell death (PD)-1 or PD-L1 (i.e., it should work best in combination with immunotherapy drugs).
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OK, I'm clogging up this thread, but just one more bit of general background. This EP4 drug that Katty is getting was developed by a Japanese (Osaka) pharma company called ONO. I actually met scientists from this company a couple of years ago when we were trying to patent a discovery that we thought could be used to develop a new inhibitor for cancer- they were the only company interested in meeting with us to get our ideas, and although our finding was too early stages for them to jump on it, but they were all over it and were pushing hard in that area .
Anyway, they are the largest pharma in Asia, and they were the ones who came up with Opodivo, which was discovered by a scientist in Kyoto. They collaborated with Bristol Myers Squibb to introduce Opodivo to the US, obviously to great success, and now they and BMS have this joint trial to try to make immunotherapy work better in many cancers, by combination with EP4 inhibitor.
Remarkably, they are also one of the oldest companies, having started as a family business in 1717, when it must have been mostly herbs and alchemy! https://en.wikipedia.org/wiki/Ono_Pharmaceutical
Terrific group, and I hope your scans look good Katty
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Cure-ious, so far no side effects to speak of other than a few minor patches of rash! I'm really trying to push water, since the protocol is hard on the kidneys.
And please, clog away! I appreciate your well-stated scientific acumen! That is remarkable information on ONO!
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Just within the past couple of weeks, two new clinical trials were announced that combine the immunotherapy, Keytruda, with an EP4 inhibitor, which is the same type of drug combo that Kattysmith is taking (Opodivo plus EP4 inhibitor). Clearly big pharma is moving fast to try out this combination, it will be so interesting to see if this works, and if so, how fast the system can move a drug along if its promising! The FDA will expedite consideration of any positive results coming from trials that include immunotherapy.
So, will ER-positive MBCs respond to this combo?! Exciting!!!
Here are links, its not clear if the trials are opened yet or just announced:
One trial for Keytruda will be open to all cancers https://www.prnewswire.com/news-releases/adlai-nor...
and the notice adds: "Based on preliminary results, it is well tolerated in patients with solid tumors. This collaboration is supported by our recent preclinical data demonstrating the potential ability of AN0025 (EP4 Antagonist) to rescue patients who do not initially respond to anti-PD-1 therapy alone or who are resistant to PD-1 inhibitors with solid tumors."
Hedging their bets, the other trial will combine Keytruda with a different EP4 inhibitor, but this trial is restricted to colon and lung cancers:
https://www.businesswire.com/news/home/20181219005...
Prostaglandin E2 (PGE2) has been shown to contribute to an immunosuppressive environment in cancer by enhancing the activity of regulatory immune cells and suppressing the activity of effector immune cells. EP4 is a high-affinity receptor of PGE2 and is known to facilitate these immunosuppressive activities. ARY-007 is an oral, potent and highly selective antagonist of EP4. In preclinical models, EP4 inhibition leads to antitumor activity and also significantly enhances the antitumor activity of checkpoint inhibitors. While in development for a non-oncology indication, ARY-007 was found to be well-tolerated in multiple studies which enrolled approximately 1000 human subjects..
The firm is highly optimistic that the proposed combination of KEYTRUDA & AN0025 (EP4 Antagonist) would be able to offer relevant clinical advantage to patients living with solid tumors.
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I’ve just confirmed this month my triple negative spread to the mediastinal nodes. Was scheduled for Abraxane /immunotherapy but cancelled my insurance didn’t approve. Schedule for a second opinion and search for trials at Vanderbelt. I.am so glad to join this site. I am clueless how looking for trials work. I’m hoping to gain knowledge and join the group in celebrating success and supporting the rocky road
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Hi Deedi, glad u found the site. It can be so helpful in finding info and emotional support. I’m also a TNBC lady and have done a few trials. Usually my MO will look for them for me as she is in the know about my case and what I can qualify for. I prefer phase 3 or higher trials, but as stage 4 am limited and have done phase 1...it didn’t turn out well and I was pulled even though I was seeing positive results cancer wise. My advice would be to talk to your MO and then research the trials they suggest. You can also do some searching on your own, but it gets a little tricky about what you qualify for and whether enrollment is open. I’ve also let my MO know what kind of trials I would be interested in just in case something comes up. If you are stage 4 it can change the kind trials you look for in that you may search for bone mets trials vs just breast cancer trials. Also as TN I’ve seen trials for lung cancer with a sub-arm for TNBC...seems very unrelated but hey options are options. Hope this helps 😊
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ChuckL- You are right, nothing listed for it yet, that just an announcement that they intend to do it. Oddly, now the link for the trial kattysmith is doing indicates that the trial is for Opodivo with CTLA-4, rather than the EP4 drug. That trial is likely restricted to those whose cancers have a high tumor mutational burden or mismatch repair defect, indicative of the rare MBCs that can respond to immunotherapy.
I am interested in the EP4-IO combo trials, and will let you know when I find one listed..
OK, this one appears to be the Opodivo plus EP4 inhibitor drug:
https://clinicaltrials.gov/ct2/show/NCT03661632
However, this trial requires that you have failed a trial involving immunotherapy as monotherapy
Nothing yet listed for Keytruda plus EP4 inhibitor trial
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Sorry to go somewhat off the OP's topic, but Cure-ious, there is something I keep wondering about that maybe you can comment on. Since I have a germline mismatch repair mutation (MSH6, a Lynch gene) would I assume the cancer would be likely to respond to immunotherapy? That it would be a microsatellite unstable cancer? My 2014 Foundation One only showed two somatic mutations, typical ILC ones in CDH1 and TBX3, and my more recent Guardant 360 only showed one with a high enough percentage to note, a Her2 mutation for which neratinib may work. I'm currently presumed NEAD on Xeloda, but of course planning my next move. My onc didn't encourage me to try a keytruda trial in the past.
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hi Katty, if you don’t mind me asking, do yours have a high tumor mutation burden? I always think that immunotherapy only works for patient whose tumors have high mutation burden, like Judy Perkins
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I have some mutation in the liver tumor cells, but "high tumor mutation" has never been mentioned. I am still ER/PR+ Her2-. I have some more specifics that I'm going to ask my doc the next time I see him. I I have scans next month that will determine if I can stay in the trial for a third cycle.
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Shetland,
Sorry I don't know enough about mismatch repair deficiencies to comment cogently to your genetic test, but it is clear in general that mismatch repair deficiencies make cancers to respond to immunotherapy , and I would seek out as many seond opinions as necessary to get a clear answer about your case, since immunotherapy could be a game-changer. I read a case study about somebody with mutations in both MSH2 and MSH6 genes who had a prolonged response to Keytruda, I think the mismatch repair state is also accompanied by high expression of PD-L1 and there are other things they can look for to indicate whether you might respond.
Although mismatch repair defects in cancers are rare, the rest of us just need a drug that will mimic a DNA repair deficient state and make the cancer become sensitive to immunotherapy. In theory, a CDK12 inhibitor would do that, and perhaps a CDK7 inhibitor might also do that, but those trials are in infancy and perhaps existing combination trials will work before then- If nothing comes sooner, there is the upcoming AACR meeting at the end of March, and the ASCO meeting at the end of May, where a lot of clinical trials report updates...
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Shetland,
Here is a link to a summary from 2017, which mentions an exceptional response in a person with Lynch syndrome.
https://www.mskcc.org/blog/science-behind-fda-s-ap...
https://www.ncbi.nlm.nih.gov/pubmed/28904067
I also realized that you might get further information, and much faster, by talking to the lead contact person of the group running the NCI "basket trial" that accepts patients with any cancer type who have DNA mismatch repair mutations.
I think there are several such trials, this one might be relevant:
https://clinicaltrials.gov/ct2/show/NCT02791334?te...
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A few months ago, someone posted a link to a fascinating article about the liver and the history of belief about the liver. Please post the link again, if you can find it! Thanks!
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Shetland, the current F1 reports have "blurbs" about each biomarker. Maybe this is nothing new. I never received my 2016 F1 full report, only a few pages. Below is the blurb about microsatellite status/potential treatment strategies from my F1 test in December 2018, in case it is helpful. I am microsatellite stable and this is the blurb for someone who is stable but based on the write-up, it sounds mismatch repair deficiencies in breast cancer are microsatellite instable 51% of the time, and Lynch-syndrome related breast cancer was found to be microsatellite instable 60-85% of the time in one small study, although these stats don't distinguish between germline and somatic mutations.
I had the new F1 report done in order to enter the NCI MATCH basket trial for another genetic alteration (FGFR1). I started this process at the beginning of December, nearly 2 months ago, and was told today it will be another 3-6 weeks to get me cleared and that I was still at "Phase 0" and have two more stages to pass. I was originally told the whole process would take 2 weeks. Glad I insisted on going back on chemo while waiting. Great trial but the red tape is a joke.
BIOMARKER
Microsatellite status
POTENTIAL TREATMENT STRATEGIES
On the basis of clinical evidence, microsatellite stable (MSS) tumors are significantly less likely than MSI-high (MSI-H) tumors to respond to anti-PD-1 immune checkpoint inhibitors1-3, including approved therapies nivolumab and pembrolizumab4-5. In a retrospective analysis of 361 patients with solid tumors treated with pembrolizumab, 3% were MSI-H and experienced a significantly higher ORR compared with non-MSI-H cases (70% vs. 12%, p=0.001)6. Pembrolizumab therapy resulted in a significantly lower objective response rate (ORR) in MSS colorectal cancer (CRC) compared with MSI-H CRC (0% vs. 40%)5.
Similarly, a clinical study of nivolumab, alone or in combination with ipilimumab, in patients with CRC reported a significantly higher response rate in patients with MSI-H tumors than those without4.
FREQUENCY & PROGNOSIS
The frequency of MSI in breast cancer varies widely due to differences in patient characteristics and sample size. In a few studies of Lynch syndrome-related breast cancer patients with small sample sizes (n<10), MSI was observed in 60%-85% of patients7-11. However, no MSI was observed in a few larger scale analysis of breast cancer samples12-13.
Moreover, MSI was reported in 51% of patients with MMR deficient breast cancer14.
Furthermore, a prospective study observed increased MSI following chemotherapy treatment, and MSI is associated with incidence of secondary tumors15.
FINDING SUMMARY
Microsatellite instability (MSI) is a condition of genetic hypermutability that generates excessive amounts of short insertion/deletion mutations in the genome; it generally occurs at microsatellite DNA sequences and is caused by a deficiency in DNA mismatch repair (MMR) in the tumor16. Defective MMR and consequent MSI occur as a result of genetic or epigenetic inactivation of one of the MMR pathway proteins, primarily MLH1, MSH2, MSH6, or PMS216-18. The tumor seen here is microsatellite-stable (MSS), equivalent to the clinical definition of an MSS tumor: one with mutations in none of the tested microsatellite markers19-21. MSS status indicates MMR proficiency and typically correlates with intact expression of all MMR family proteins16,18,20-21.
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Cure-ious and JFL, your replies are very helpful. Thank you. I will try to post more later.
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thanks Katty! I’ll ask the doctor about your clinical trial too
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