Are you currently (or have you been) in a Clinical Trial?
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for PI3KCA mutant cancers, and update for RLY-2608 was provided this morning-
PFS 9.2 months, ORR 33%. For kinase domain only (H1047 mutants): PFS 10.3 months, ORR 53%
They will open a trial including a new CDK4 inhibitor from Pfizer this year, and start phase 3 in 2025 where the comparison will be Capivasertib (Truqap; PFS 5.5 months)
https://edge.media-server.com/mmc/p/va3nrjyv/
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I’m at a trial consultation now. I can start a vaccine trial by end of month or a cdk2 or aurora a in October. I think vaccine is the way I’m going. 3 arms: vaccine; vaccine plus a keyteuda type drug; or Dr choice (gemzar).
Any opinions?
Thank you!
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cure-ious thank you for sharing such useful information, really help me in searching for promising trials.
I found a few trials like VERITAC and TACTIVE study on ARV-471 with or without CDK, but unfortunately I was disqualified simply because I have already started Elacestrant, such a disappointment. when they say “exclusion,” it feels like a hard, non-negotiable rule. I was told that the criteria are restricted because of statistical purposes, they want to maintain consistency in their study populations but it's hard when those restrictions keep us from accessing potentially life-saving treatments. the trial that perky is on at Cedar Sinai is no longer recruiting.
Is there any way to be reconsidered for a trial despite being excluded? I’d love to hear everyone's experience or opinion on this. Thanks
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I do not know about avoiding exclusions, your MO could try calling the trial doctor, they for sure listen to the MOs.
I was noticing that both the KAT6-faslodex trial and the RLY-faslodex trial have a limit on not more than three lines of therapy, including any lines of chemo. Which means if you have had two or three lines already, you would have to pick between these trials, which seems really unfair given that they are completely unrelated and both have really good numbers.
The one silver lining is that companies do tend to add new lines or trial extensions, as RLY-2608 will be doing this year, which can include additional sites where the trial is offered and change out the restrictions, sometimes allowing for more prior lines of therapy, etc
With respect to ARV-471 disallowing Elascestrant that is also seems unfair, not only are these are completely different mechanisms but earlier trials with oral SERDs even allowed prior therapies of different oral SERDs (and they got responses too). It seems phase one trials are more open, then when they get further along ( and more $$$ are on the line) they want to cherry-pick the patients a bit more to give better numbers.
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And for ARV-471, they better find a way not to exclude people who were on Elascestrant because they are really going to lose a lot of their potential patients, no? It is possible they could do BETTER with people who already took Elascestrant, because those people will have cleared out the ESR1 mutants..
Anyway, I hope someone chimes in on "compasionate use" of drugs, because our MOs can ask for permission to use these drugs if we don't have better options and are excluded from trials.It is also to our benefit for more people to use clinical trials so they accrue faster and open up more arms. I noticed that one phase 3 trial filled up with 900 patients in a year, so there are a LOT of us!
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CBLaurence,
Is this the vaccine trial at Hutch? I wondered about these trials, if you are allowed to go off and try another therapy while they are preparing your vaccine… What mutations does the cancer have? I know both CDK2 and Aurora A are getting good numbers..
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Oh, that's an excellent question. It wasn't explained to me as being individualized—hmm…I might have to ask about that because I can't be without some kind of treatment for too long. I don't have any targetable mutations unfortunately. ER+ and Her2- (0).
I may have to ask the doctor about a bridge chemo if I have to wait. The CDK2 and Aurora A are great alternatives, but they don't have openings for a while.
We have the ball rolling on the vaccine, but I'll email now and see if there's a wait on the actual vaccine itself. If I'm randomized into the chemo arm, then I really don't want to stay in it, and I'd try to move to another trial if I'm allowed to do that.
So many questions! I'll keep you posted!
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So the vaccine is not personalized and is a phase III trial. Now my only hurdle is my regular oncologist, because the trial people are aiming for an October 1st start date (not a guarantee) which will be 33 days past my last treatment. I have a message into her to see if she thinks that is too long. I'm okay with it since I had a mixed result on my last scan—I don't think it's growing fast enough to be a huge concern, although my liver is covered "innumerable lesions". Fingers crossed!
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@cblaurenceauthor Which phase-3 vaccine trial are you referring to? Is it Her2-targeted? Thanks!
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Here's the info! :)
Study of the Bria-IMT Regimen and CPI vs Physicians' Choice in Advanced Metastatic Breast Cancer. (BRIA-ABC)
ClinicalTrials.gov ID NCT06072612Sponsor BriaCell Therapeutics CorporationInformation provided by BriaCell Therapeutics Corporation (Responsible Party)Last Update Posted 2024-08-26
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Thank you! Exciting. Good luck! (As a bridge therapy, you could try high-dose estradiol. I’ve done it and it was very effective. 2 mg three times a day.)
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Ha! I was just coming now to ask if it was the new Bria-Cell IMT trial!!!
https://clinicaltrials.gov/study/NCT06072612
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Also, and this is a general question to anyone who knows about this, can't you start a therapy and then if you decide to discontinue it _say for side effects or fatigue or whatever- then its OK to move forward to something else? I think clinical trials only take you on progression, for example, in case it doesn't work you don't then blame them for making you leave something that was working, but that its fine if you decide to drop the therapy. so long as it doesn't make you have too many treatments or too many chemos to then qualify for the trial?
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Summary of BriaCell-IMT results in phase two:
Phase 2 clinical data of the Bria-IMT™ regimen in 54 advanced metastatic breast cancer patients who failed multiple prior treatments, including ADCs and immune check point inhibitors (CPIs) (median of 6 prior treatments) are presented:
Median progression free survival (PFS) of 4.1 months in heavily pretreated ADC resistant patients, which is double the response of physician's choice
Overall response rate (ORR= tumors shrinking) of 9.5% and clinical benefit rate (CBR= those who respond are stable for at least 6 months) of 55% in evaluable patients
5/6 (83%) of evaluable patients (one inevaluable) with intracranial lesions treated with Bria-IMT™ in all BriaCell studies had intracranial responses, including complete and partial responses
Therapy was well-tolerated with no Bria-IMT™ related discontinuations. Absence of both interstitial lung disease (ILD), a common serious adverse event with ADCs, and Bria-IMT™-related treatment discontinuations underscore Bria-IMT™’s excellent tolerability and favorable safety profile.
In conclusion, improved progression-free survival and clinical benefit, along with an excellent safety profile, were observed in heavily pre-treated advanced breast cancer patients versus literature reported data in other similar studies. BriaCell will continue to monitor these clinical responses in its current pivotal Phase 3 study of Bria-IMT™ and CPI in advanced metastatic breast cancer.
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I was just looking for results information. It doesn't look all that impressive to me. I wonder if the Aurora A or CDK2 has better results? Not that it really matters, I'll have to do this one first because the others aren't available until October, but once this fails (which appears to be faster than I'd like, :)) I might be able to jump onto a different one.
Thanks for posting!
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CBL,
It could be that it should be given earlier, its a safe choice and clearly better than old-time chemo.
But now is a good time to update where these other drugs are at- and did you consider KAT6A/B or CDK7?
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The phase one Pfizer KAT6A/B histone deacetylase inhibitor (epigenetic drug; PF-07248144) results were just published in Nature Medicine in June. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2− mBC. It seems to work just as well on ESR1 and PI3KCA mutant as the unmutated cancers, which is unusual. However they saw significant SEs: Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Dysgeusia (bad taste or metallic taste) is apparently a common feature of the epigenetic drugs. But as they argue in the paper their results look as good or better than those seen for Elascestrant or the PI3KCA inhibitors…
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There is an interesting trial combining the CDK7 inhibitor Samuraciclib with ARV-471, the ER-PROTAC that degrades the estrogen receptor, as an arm of the TACTIVE-U trial. First patient was dosed earlier this year:
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Here is a poster summarizing the latest BLU-222 CDK2i results, however its so early all they can say is when combined with Fulvestrant and Ribocyclib, they saw reductions in tumor markers. Apparently CDK2i should be given with a CDK4i as the kinases can substitute for each other. Not sure why its taking so long to get a good CDK2i, must be tricky cuz they have been at it for awhile now.
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But Pfizer is further ahead with a CDK4-selective inhibitor, 4x stronger than Verzenio which apparently can work on CDK4.6i-resistant cancers. They have a phase 3 trial started for that with Fulvestrant and will open up a trial combining it with the RLY-2608 PI3KCA inhibitor drug.
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Hi @cure-ious
Yes, I suppose the heavily treated aspect is a big part of it. I've been through 5 lines (kisqali/fulv, everolimus/exemestene, xeloda, trodelvy, halaven) so I probably qualify for heavily treated or close to it anyway.
I'm sure the other trials are available at MD Anderson or San Antonio, but I'd have to fly there which is doable, but such a pain and I get sick on planes. That CDK4 from Pfizer sounds cool—I don't have many opportunities for phase 3 trials like the vaccine.
My only stumbling block now is my oncologist approving a 33 day wait in between treatments. Yikes! That's a long time, so we'll see. The target date to start is October 1st—I'll keep everyone posted.
Thanks for posting!
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Here is a full review of the recent data on RLY-2608 for Pi3KCA mutant cancers:
https://www.onclive.com/view/rly-2608-fulvestrant-yields-early-clinical-activity-in-pi3k--mutated-hr-her2-breast-cancerolid-tumors?utm_source=www.onclive.com&utm_medium=personalizedContent
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ESMO 2024 starts Friday. There will be a session on PI3KCA mutant MBC, plus of course updates on CDKis:
In a session on development therapeutics, Timothy Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center in Houston, will present data on a first-in-class novel combination trial of a next-generation cyclin-dependent kinase 4 (CDK4)–selective inhibitor (PF-07220060) and a next-generation CDK2-selective inhibitor (PF-07104091) in patients with hormone receptor–positive, HER2-negative metastatic breast cancers and advanced solid tumors (618MO).
The CDK4 inhibitor “has basically dialed out the CDK6 inhibition, which brings with it a lot of the toxicities like myelosuppression,” Dr. Yap told ONC. In previous studies of the drug as monotherapy, it was shown to have efficacy and to be “much better tolerated” than CDK4/6 inhibitors.
“A big challenge with these CDK4/6 inhibitors that are approved is that we don’t have anything for our patients once their disease progresses. What are we going to do for these patients once they are resistant to the drug?” Dr. Yap asked.
The other treatment, PF-07104091, was developed on the basis of the observation that patients who experience disease progression on CDK4/6 inhibitors have tumors that overexpress CDK2, making it an attractive target for a follow-on drug, he explained.
“What we’re going to present for the first time – and what’s so exciting – is that we have actually combined the CDK4-selective [inhibitor] with the CDK2-selective inhibitor, and this is for [estrogen receptor]–positive breast cancer patients. So, this is a real unmet need. We’re going to show efficacy in patients who already progressed on palbociclib [Ibrance], ribociclib [Kisqali], and abemaciclib [Verzenio],” Dr. Yap said.
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The BRIA-IMT vaccine is today reporting an almost doubling of overall survival for later stage MBC (5+ therapies)
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That's exciting! I think. ;)
Maybe I'm being dense, and I've googled it, but if the PFS is 4.1, and the OS is 15.6, then what does the vaccine have to do with the OS? I mean, if I progress after 4 months, then presumably I go to different drugs that will keep me going for the remaining 11.5 months. I'm not understanding the purpose of OS in relation to a specific drug.
Anyway, I find out Tuesday which arm I've been assigned. If it's the SOC drug, I may not do the trial at all and opt for a different trial where I'm guaranteed an investigational drug. I don't want to pass up an opportunity for another line since I only have a few left.
I need to ask a few questions of the trial docs:
- Will I have access to my bloodwork/scans results?
- Can I take Gemzar for a round or two while waiting for the Aurora A or CDK2 trials to open, then go back to Gemzar after I progress at some point?
I'm sure there are more but I can't think of any right now. Sigh. My poor brain.
Thanks for posting the update and I'll update on Tuesday when I know.
CBL
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My last guardant test showed my MSI (Microsatellite Instability High) is low which I think means immunotherapy is unlikely to work for me. Does anyone know if this would make a difference with regard to BRIA IMT Vaccine?
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CBL, I wish someone who follows these terms better than I would weigh in! i have the same kind of question about some immunotherapy regimens, where they see improved overall survival, something that is typically so hard to show for most of our treatments, even as the PFS itself doesn't look so impressive. I imagine that it means the therapy continues to help with subsequent lines of treatment, maybe just due to generally improved overall immune activity? If so, shouldn't we all get this, because it is forward progress, regardless of how long it works as a standalone treatment?
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Sounds reasonable. I'll ask at my meeting on Tuesday. Maybe someone can make it make sense!
CBL
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Chico, I did read that MSI high is rare, but it is not a requirement for immunotherapy (IO). Tumor mutation burden is another indicator they use, and most of those (like 70%) do not have high MSI. However the TMB we get on a Guardant profile does not correspond to the TMB that is measured in a tissue biopsy, and for IO they follow the tissue TMB, which is like 5X higher than what is measured in a blood biopsy. So what number is good? Even tho FDA considers a tissue TMB=10 to be high and qualify for immunotherapy, the level that works is apparently different for different cancers. For MBC, one study said the threshold is higher, like 14-16, with the majority of those at that level (60+%) responding to IO compared to only 6-8% for people below that level. That means we want the Guardant blood biopsy TMB level to be about 70, and one oncologist told me 90 is what she looks for…
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Plus note the BRIA-IMT says the overall response rates in the hormone-receptor–positive, HER2-positive, and triple-negative breast cancer subgroups were 10%, 50%, and 0%, respectively.
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