Are you currently (or have you been) in a Clinical Trial?
Comments
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Updating (my overly-simplified explanation); ARV-471 is a pure degrader- it has a link that brings the destruction complex right to the ER, it cannot escape. No need to inhibit its activity. Resistance should be very different than types of resistance that would develop to a CERAN-type SERD. Very cool.
Here is a good review:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC80477...
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Updating (my overly-simplified explanation); ARV-471 is a pure degrader- it has a link that brings the destruction complex right to the ER, it cannot escape. No need to inhibit its activity. Resistance should be very different than types of resistance that would develop to a CERAN-type SERD. Very cool. Maybe we end up with multiple useful treatments out of all this work.
Here is a good review:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC80477...
Note: "PROTAC-induced rapid and complete degradation of ER protein eliminates any ligand-dependent (AF2) or ligand-independent (AF1) agonism. PROTAC action is event-driven as opposed to occupancy-driven in the inhibitory setting; thus, only a transient binding event is required for degradation, and the PROTAC molecules can cycle through multiple rounds of activity, removing substoichiometric quantities of proteins."
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Wow, I learn so much from this board! Thank you all for your responses, especially you, Cure-ious! This trial allows prior use of AIs and/or fulvestrant, which shows they think this drug potentially overcomes endocrine resistance.
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The PACT Pharma trial is: https://clinicaltrials.gov/ct2/show/NCT03970382. It is a phase 1a/1b trial in solid tumors, so very early days.
I don't have much more specific trial information than what is listed in the trial description, but will let you all know when I learn more. It is a many step qualification process, so I am still in the prescreening phase, although identifying cancer mutation targets (neoantigens) was a big step in the qualification process. I gave them blood and tissue samples for that purpose months ago. I can confirm that originally they were going for one antigen, but now they look for up to three. Also, they are not yet using nivolumab in the trial. The PACT Pharma trial allows you to pursue any and all treatments (including other trials) while you are going through the pre-qualification process for their trial.
I had chemo (eribulin) yesterday, so I'm not feeling well today and am going to try to take a nap.
Best wishes to everyone! Theresa
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Theresa this is so exciting. I hope you get good rest.
Husband- happy dance 💃🏻
Cureious-thanks for even more info on my trial ARV 471. You are a great researcher. I did ask Dr Hamilton about how people are responding on the trial- she said it has someone at 20+ cycles. But also some who are off because they did not respond.
the CERAN study was on my list at Sarah Cannon. I did not meet eligibility at that time- probably my IVIG infusions. The trial's 4 week flush is on the longer side- many trials are at 2 weeks. I can ask about how it is going next time I am there if you are interested.
Dee
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Dee- Yes, please ask especially as that trial is only available at a couple sites in the US, tho should be noted there are also several sites in Australia, clearly the drug is originating from there
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Does anyone know anything about treatment targetting ROR-1?
I'm looking at this trial at Fred Hutch Seattle which has an arm for mTNBC. It's a CAR-T trial from what I can make out but you need ROR-1 expression to be >20%. https://clinicaltrials.gov/ct2/show/NCT02706392
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MOTH - there is another trial targeting ROR-1
A Study of VLS-101 in Patients With Solid Tumors NCT04504916 https://clinicaltrials.gov/ct2/show/NCT04504916
antibody- drug conjugate (ADC) that targets receptor tyrosine kinase-like orphan receptor 1 (ROR1) on cancer cells
“ROR1 is a cell-surface protein that has an important role in the formation of the nervous systems, bones, and blood vessels during the early development of the embryo.ROR1 disappears by the time of birth and is not detected on normal human tissues in childhood or adulthood. However, ROR1 can reappear on malignant tissues, including on hematologic cancers. This selective expression of ROR1 on cancerous cells but not on normal cells offers the potential for using VLS-101 to specifically kill the cancer cells while sparing normal cells.
VLS-101 is an investigational drug consisting of a monoclonal antibody that binds to ROR1 coupled with a potent toxin called monomethyl auristatin E (MMAE). After the antibody binds to ROR1 on cancer cells, the ADC can enter those cells, where the MMAE is released and can destroy the cancerous cells. In mouse models of human solid tumors, VLS-101 has caused highly significant tumor shrinkage.”
I was offered this trial at MDACC, but chose to go with ARV 471. I will keep it in my pocket though.
Hope this helps.
Dee
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Moth, Great trial- ROR1 is reported to be highly expressed in TNBC, where 56% of samples were graded as ROR1-high. Almost none in normal tissues. As Dee points out, this is one of those proteins expressed transiently during development then shuts off in the adult, only to be re-expressed in cancer.
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ok great thx for your input! I will pass it on to my oncologist when she comes back next month.
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However, I was just reading a note of caution, both for ROR1 as a target in breast cancer, and for CAR-T as the approach- need to see what the results of this trial have been thus far.
https://seekingalpha.com/article/4435695-oncternal...
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So, Moth, here are some results using a monoclonal antibody to ROR1 together with paclitaxel chemo. Of 15 patients that had been heavily-treated, one was on therapy for a year and four were stable for six months.
Trial Update Results reported at ASCO-2021:
- Poster Title: A Phase 1b Trial of Cirmtuzumab and Paclitaxel in Locally Advanced/Unresectable or Metastatic Her2 Negative Breast Cancer (Poster #LB255)
- In this Phase 1b investigator-initiated clinical trial from the University of California San Diego (UC San Diego) School of Medicine, 15 patients were treated with cirmtuzumab and paclitaxel after receiving a median of six prior therapies for metastatic disease. Of 15 intent-to-treat patients as of April 10, 2021, eight patients (53%) had a best response of partial response (PR), one of which remained durable for 52 weeks, and four patients (27%) had stable disease (SD). Of the 14 patients who were evaluable for efficacy per protocol, eight patients (57%) had a PR and four patients (29%) had SD. All reported adverse events were related to paclitaxel except for one Grade 3 neutropenia that was categorized as possibly related to cirmtuzumab. No patient stopped cirmtuzumab due to toxicity, no dose reductions of cirmtuzumab were required and no dose limiting toxicities were observed. The authors concluded that as of the cutoff date, cirmtuzumab given with paclitaxel was well-tolerated and demonstrated no added toxicity over what was expected with paclitaxel alone in heavily pre-treated patients with metastatic breast cancer. As of the cutoff date, all pre-treatment breast cancer samples available for analysis expressed ROR1 as assessed by immunohistochemistry. The authors concluded that further clinical evaluation of cirmtuzumab was warranted in patients with breast cancer.
PS I didn't see any results yet for VLS-101, the ADC Dee is talking about, but its probably just too new0 -
cureious
From the article you listed - “However, it's crucial to remember that just because a cancer expresses high levels of a protein (like ROR1), does not mean that the cancer requires the pathway for its survival and growth. Just because a protein activates a pro-tumor pathway, does not mean the cancer actively uses it for its survival.”
Isn’t that the issue with many cancers- they don’t know what is driving it? That’s why we keep trying different drugs with different mechanisms.
I have 2 RESIST tumors that are heterogeneous. The larger one is hypervascular and is fluctuating(mostly up) by only a few mm on my trial drug. It grew while on cdk2/4/6 by 1.2 cm. Clearly ARV 471 is halting the progression rate. The smaller one is low density and shrinking quite well. If this wasn’t a trial, I would be zapping the larger one with y-90 (and I asked). So My cancer must be at least partially driven by estrogen since the PROTAC is working toa degree
I have receptors for the Neuroendocrine part that has a treatment. It would be off label and experimental but I have done a lot of research and outreach so It is in my back pocket. But since I am responding to my current therapy I wonder if I would benefit from the other. Cancer is so tricky.
Dee0 -
Hi Dee- Are you trying to decide when to try adding something else? if they aren't threatening to kick you off the trial, you must be doing well. But its true if you have something else you want to try, you have to decide when to add it in. but first, make sure it won't interfere with what you are taking, and maybe save it for when you are between treatments? Beyond the neuroendocrine part, are there other things that could help?
I take pitavastatin, even tho my cholesterol is OK, because it has exceptional anti-cancer activity and kills cells that have low levels (or lack) the PTEN tumor suppressor, a common problem in breast cancer. PTEN loss is associated with PI3KCA activation and endocrine resistance. You just reminded me that the i-3-c supplement actually boosts the level/activity of PTEN, by inhibiting an enzyme that degrades it. It's the stinky supplement derived from broccoli- I'm going to start taking that again, because it ought to play well with the pitavastatin.
https://science.sciencemag.org/content/364/6441/ea...
https://www.sciencedaily.com/releases/2020/03/2003...
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Cureious-
No changes yet. I am going to stay on ARV 471 and ride it for as long as possible. Just wish I could get the Y-90 to the bigger tumor now. It’s weird to have a walnut size tumor just hanging out.
I’m trying to enjoy stable disease and not worry about what is next. But I do like to see the latest science!
pitavastatin is approved by my trial but not my insurance and it is more than $300 per month. I will stay on Crestor. I do not have PTEN loss according to TEMPUS.
Dee
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hi all!
Wow alot has gone on this thread in the few days I was gone! I will go back & read.
They have dose reduced me by ½ for the trial drug, so once a day. I started it yesterday at chemo & fingers crossed no rash yet or even itching.
At chemo even with the extra premed intravenously & steroids I had a reaction but I recognized it very early & we were able to stop the infusion immediately. While I had a hard time breathing, muscle cramping to legs and back and my face was as red as my bright red dress, it wasn't nearly as bad as the first 2 times plus I had one of my old RN's from Nanaimo where they do things way more patient centric and she was way better than all the others I've had in Vancouver. She sat with me the whole time watching, not wandering about not paying attention.
My MO came in to see me and make recommendations so all in all they gave me 3 doses of benedryl and a bunch of other things that I can't remember. My MO is going to ask the trial if we can try Abraxzane? Apparently fewer of these issues.
I had the best nights sleep I've had in weeks because of the benedryl crash & a sleeping pill which i took because of all the steroids. Boy sleep in so underrated, I feel like a new woman today. Oh that & my TMs have fallen by 270 pts, 790 to 520 even tho I have missed quite a bit of time on both chemo & the trial drug, so I will just keep at it & hope this is just the "beginning a new treatment blip"
Thanks for all your support, I appreciate it so much, cheers, dee
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Dee - Glad to hear things are heading in the right direction even though that last infusion was still a nail-biter. I hope you get to switch to Abraxane. Happy to hear the good news on your markers!
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GG27/Dee, I love that you wore a red dress to chemo. Any chance you can schedule future infusions to be when your great RN from Nanaimo is on duty? Yay for sleep and falling TMs!
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GH27/Dee- nail biter indeed. Yay for sleep!
I think that you should celebrate with a Nanaimo bar- I have perfected a recipe to my liking and luckily when I make them I have plenty of takers.
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I'd like one, please.
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This is fantastic news about the FDA trying to open up trials to more people! Weird that they seem to be more concerned with exclusions of people who haven't had enough treatments. I am usually excluded because I have had too many treatments.
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Sorry for cross-posting
Does anyone know the clinical trial based on [177Lu]-NeoB administered in patients with tumors that have GRPR (overexpress gastrin-releasing peptide receptor)? I now have a chance of being in this trial. The treatment with Lu-NeoB is to use the radioactive molecule (Lu) that can destroy the cells overexpressing GRPR. Before Lu-NeoB, patients will be administered with Ga-NeoB to see if their tumors carry GRPR. If the Ga-NeoB test is negative, the trial will be discontinued.
A quick background about me: this March, I had undergone 4 lines of treatments within 7 months, and the 4th line failed at the time. And my liver tumor size was about 9cm then and grew continuously. In April, my MO and IR discussed, deciding to use SBRT (it is not 100%SBRT though, more like low-dose SBRT). In 3 months, the tumor has shrunk to 2.7cm. There are currently other small liver tumors that the SBRT didn't and couldn't target at the time. I know clearly that I cannot have radioactive treatment to the liver again in a short period of time. My MO was surprised that my tumor is so responsive to the radioactive treatment. Recently, she shared the above clinical trial info. with me, and thinks it may be beneficial to me given the efficacy of my prior radioactive treatment.
I asked my IR what this Lu-NeoB clinical trial really is and what is the catch of it. He said some people called it radiopharmacy, which combines both benefits of radioactive and chemo therapy. One research project (see the link below) using the similar logic of treatment in prostate cancer clinic trials phase III with significant success, just published a few days ago in 'the New England Journal of Medicine' (one of top-tier medical journals, I know the journal is very reputable when he mentioned).
https://www.nejm.org/doi/suppl/10.1056/NEJMoa2107322/suppl_file/nejmoa2107322_appendix.pdf
The new treatment of the trial I am offered is different from Y90/SBRT/Ablation, cause it goes through the whole body not just liver. My IR thinks this treatment is promising and expects there will be more and more similar clinical trials coming out very soon. In fact, I was offered with another clinical trial (same logic but targeting with different kinds of protein receptors of cancer cells). If you are interested I can share it here.
Next week I will discuss with the clinical office people and the primary investigator doctor for more detail. A no-brainer question is that this clinical trial is still new in the area of metastatic breast cancer. I wonder if any of you have ever heard of this or participated in the trial (other similar types of trials are fine too). Thanks
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Sac321 - no worries about cross posting. We understand! I responded on the liver thread.
Dee
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Ever more precise data accumulates on the molecular changes in MBC, from a new paper in Cancer Discovery:
The 381 patients included in the initial report came from 51 centers in nine countries. With regard to breast cancer subtype, 247 (65%) patients had HR-positive/HER2-negative tumors, 72 (19%) had TNBC, and 60 (16%) had HER2 breast cancer. Almost a fourth (23%) of the patients had de novo MBC.
Overall, 88% of point mutations in driver genes occurred in both the primary tumor and the metastasis. In 10% of cases, at least one point mutation was acquired in metastases. Metastases were enriched with point mutations in ESR1, PTEN, CDH1, PIK3CA, and RB1. SNP analysis identified copy-number variants in 31% of the metastases. Metastatic lesions more often had copy number gains (amplification or over-expression) of MEM4, MYC, NSD3, FGF41, AXIN1, TSC2, FLT4, NTRK1, and N4BP2, as well as deletions of ARHGEF10L, CASP9, RB1, ARID1A, and PBRM1.
https://www.medpagetoday.com/hematologyoncology/br...
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Hi curious & dee
CERAN is yet to recruit in Australia but sites in USA are in recruiting. See here for more detail: https://clinicaltrials.gov/ct2/show/NCT04505826
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Cross posting. Oral paclitaxel may still be a future option despite being denied FDA approval a few months ago. "The FDA was supportive and encouraged the Company to continue development of oral paclitaxel and encequidar for the treatment of metastatic breast cancer. The FDA also agreed that a well-designed and well-conducted trial may adequately address the deficiencies raised in the CRL." https://www.obroncology.com/news/athenex-provides-update-from-fda-type-a-meeting-regarding-oral-paclitaxel?ap=334&vhid=
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hi all!! (cross posted from week paclitaxol for stage IV)
Well 4th infusion, 4th anaphylaxis reaction. First & second week it happened 3 minutes into 100%, third week 3 minutes into 75%, this week it was 3 minutes into 50% & that was with extra premeds of 20 mg of prednisone X 2 doses. So not sure what the plan is, but i'm done with paclitaxol. I think she might try nab-paclitaxol. I think that's the only other drug allowed on the trial.
cheers, dee
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GG, nab-paclitaxel is super easy from an admin standpoint. I'm bummed for you they tortured you so many times before letting you switch .. it is a lot more expensive so maybe that's why. But anyway, it's a fast infusion (30 min + 10min rinse), no premeds. The only issue with it is that pharmacy takes *forever* sending it up. Apparently it's hard to reconstitute because it doesn't want to dissolve but you can't shake it because it bubbles so it has to be gently massaged into the solution.... Only thing is that BCCA wouldn't let me go weekly on it, only q21 days. Apparently it's so expensive and they'd have to waste the vial if it's divided into smaller doses that it wasn't an option.
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GG27 - How scary for you. I sure hope nab-paclitaxel is the solution.
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thanks Moth for all your knowledge about this stuff. I don't know what the actual plan would be, but the 6th floor Dr on call said that was what he thought we would go to, but I don't think he has any knowledge of what the trial will or won't allow.
and thank you KarPC for your kind words, I hope so too.
Going to try to get some sleep tonight, last night was a wash, with all those mg's of steroid coursing through my body, I was quivering most of the night. I kept waiting for the benedryl crash which never came.
cheers, dee
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