Time-limited Pirtobrutinib triple for treatment naive CLL or Richters at M.D. Anderson

[SeymourB]

clinicaltrials.gov/ct2/show...

After several false starts, we're driving to Houston next week for the pre-trial screening blood tests, CT, and bone marrow biopsy. I think Dr. Thompson was a bit too optimistic before he left MDA, thinking it would happen in November 2022 or January.

I finally got a copy of the actual protocol document, and made contact with the Study Coordinator to nail down dates. At this point they have a couple dozen of the planned 60 participants. Since this is only happening at MDA, I expect it will draw patients mostly from Texas.

We will be commuting each week from New Orleans, Louisiana, and hope to get some financial help with hotels and insurance costs. I will be applying to the Leukemia Lymphoma Society for co-pay assistance as soon as I'm accepted, as well as asking MDA to ask my insurance company for an Out of Network Exception. LOXO/Lilly is paying for the Pirtobrutinib, but I haven't seen in writing who pays for anything else.

I have the impression that once the trial gets going, there will be fewer problems for new participants as well as for my own participation.

The protocol is not identical to the NCI document that was published on cancer.gov that I posted earlier. I suspect that was an early draft and may be updated soon.

The actual protocol still has 2 arms - 1 for treatment naive, and 1 for Richters Transformation patients.

It calls for:

28 day cycles (this is standard, I believe)

Clinic visits every week for the first 2 cycles, and then every other week for the remaining cycles.

7 cycles of pirtobrutinib

6 cycles of Obinutuzumab, 1 infusion per month, with 4 infusions the first cycle (day 1, 2, 8, & 15) . The first infusion is the partial dose, and the remainder on day 2. I think that's fairly standard. But I get the impression that by not doing a day 22 infusion, and not repeated the weekly in cycle 2 means this is less aggressive than standard V&O.

6 cycles of Venetoclax starting , cycles 2-7, with a 5 week ramp-up

Allopurinol to combat TLS kidney effects during the first 2 cycles

Valaciclovir to try to prevent latent virus reactivation (VZV/shingles, HSV-1, HSV-2, and possibly others).

After 7 cycles for treatment naive, a final bone marrow biopsy. Bone marrow biopsy after the 1st, 4th and 7th cycles for Richters arm.

If no response after 7 cycles, an additional 6 cycles of Pirtobrutinib and Venetoclax will be given. The protocol document does not mention MRD testing. They do not define "response"in the protocol document like they do on the clinicaltrials link above. I will be asking about that.

Follow-up for 5 years for treatment naive, roughly every 3 months for 2 years and then every 6 months.

If you're interested:

Leukemia Clinic Main Number: 713-792-8760

Email: [e-mail]

=seymour=

[AussieNeil Partner Administrator]

Good to see that you are finally on your way on what looks to be a well thought out trial design. I expect you'll do well, though I don't envy you the gruelling travel requirements early in the trial.

Neil

[SeymourB in reply to AussieNeil]

AussieNeil -

Well, the egg has not hatched just yet. We're excited but also anxious. This will really slam my system pretty hard, I think. I don't think I'm as bad off as many of us in Watch & Wait. My nodes are not that swollen, though my spleen is enlarged. I have this slowly growing lump on my face, and significantly increased fatigue, plus many abnormal lymphocytes. I had a flow in December that ruled out Richter's for now. HgB is 13, but platelets and RBC's are still normal, though trending noticeably down. I'm increasingly breathless on exertion, but I think I'm still RaI stage II.

=seymour=

[cajunjeff]

Seymour, that’s a fairly intense trial. I can only imagine this is a go for the Cll kill shot trial for treatment naive and Richters. Similarly designed trials with ibrutinib instead of pirtobrutinib have had lots of people getting into deep remissions and getting mrd negative.

A significant number of people taking Fcr have never relapsed, leading to the speculation that they are cured. I think they are cured just based on how remissions work with other cancers, that is, if you haven’t relapsed in ten years, you probably will not relapse ever.

It’s reasonable to assume that those people who achieve mrd status and deep remissions in your trial might also be cured.

I hope you will post your experiences with your trial. I’ll be at MD Anderson in March and if you are around, I’ll buy you lunch. I’ve met a few of our members on here at MD Anderson.

We are renovating our condo in New Orleans warehouse district and hope to get back to New Orleans more often. The renovation is supposed to be done the day before Mardi Gras. Lol. It will take us a few weeks after that to get our furniture back in. I haven’t been to a Mardi Gras parade since Covid.

Good luck with your very exciting trial, I can’t wait to read your post about being MRD negative, fingers crossed.

[SeymourB in reply to cajunjeff]

cajunjeff -

I've looked at the IVO and AVO trials. and they were actually longer than this one. MDA are still doing an AVO trial:

clinicaltrials.gov/ct2/show...

Acalabrutinib and Venetoclax With or Without Early Obinutuzumab for the Treatment of High Risk, Recurrent, or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

It's a mininum of 15 cycles, with an option extension to 26 cycles.

There is also ZVO trial (Zanubrutinib) that only goes 8 cycles, but not hosted near me:

clinicaltrials.gov/ct2/show...

Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL)

=seymour=

[johnliston]

Seymour, I did the I/V trial down there. The only thing the trial paid for was the Venetoclax which was the trial drug. Every thing else medical was paid for by Medicare. Except my Ibrutinib copay which was picked up by PAN. I got help from the American Cancer Society with Motels either free or reduced rates. LLS has a travel fund seperate from their copay fund which might be able to give you some travel money. I had to travel down every week during ramp up, so these funds helped. Unfortunately, LLS and PAN periodically run out of funds and that might be the case at the moment.

Good Luck John

[SeymourB in reply to johnliston]

johnliston -

Thanks, John!

We've looked at each of those, and just got started on my taxes, since some of them want to know our gross income. Sadly, we have to take withdrawals from the 401K retirement savings to pay medical bills, and that, too, accounts as income, unless I can find a clause that would exclude that. LLS doesn't go by AGI - adjusted gross income.

I think that since insurance deductibles go into effect in January, everyone in the U.S. pays a lot more out of pocket in January and February, and that may deplete the assistance funds more quickly. So we'll just deplete the 401K more. If I could get energy and mental clearness back consistently, I might even go back to work part time.

=seymour=

[GumboKing]

Terrific Seymour,

We will be pulling for you as well as all trial participants. Please keep us posted.

Paul

[HopeME]

Hi Seymour:

It will be interesting to see what they mean by “If no response after 7 cycles an additional 6 cycles of P & V will be given? It’s got to mean if not MRD- ?

You mention below this will really slam your system. I’m doing something similar (V + O) without the P and it really hasn’t been bad and I had a heavy cancer burden in my marrow. Yes a lot of appointments and infusions but the physical impact has been minimal. Mentally driving into the hospital some mornings has been draining but physically it’s been relatively easy. My main point is you might be surprised how well you do with this treatment so don’t psych yourself out 😀. You will do fine once you start. We always envision things worse that they turn out to be.

Best,

Mark

[SeymourB in reply to HopeME]

Mark -

I think the Protocol Document goes by the standard iwCLL response definitions for complete response and partial response.

But the ClinicalTrials info says:

"Primary Objective:

1. Estimate the therapeutic activity (undetectable measurable residual disease [U-MRD] rate) of combined pirtobrutinib, venetoclax, and obinutuzumab in patients with previously untreated CLL/SLL (cohort 1) by undetectable measurable residual disease (U-MRD) rate and Richter transformation (cohort 2) by overall response rate (ORR) (defined as CMR//PMR)."

I see the Protocol Document as being written for patients, and legally worded to allow reaction to AEs, among other things.

The ClinicalTrials info calls for "U-MRD response with next generation sequencing assay for cohort 2" (the Richter's cohort), which I take to be ClonoSEQ, but not for the CLL naive treatment patients. They get either MRD 10K or 100K. I think I would pay out of pocket for ClonoSEQ if I had to - it's "only" about US $2K. I really like the additional data.

My wife is the pilot for driving, and I'm the navigator. Our weekly drive will be about 400 miles each way. We plan to drive 3 hours, then have lunch near the Evangeline Oak in St. Martinville, Louisiana, with a walk along Bayou Teche. Then another 3 hours into Houston before the rush hour traffic.

=seymour=

[HopeME in reply to SeymourB]

Thanks for the additional comments on testing. They are interesting to me as I read somewhere recently that the standard of care for the treatment (V + O) I’m having doesn’t include deep (colonalSEQ) MRD testing. That being said, as you may recall I am on a clinical trial for the ramp up of my V (done over a week in the hospital) that runs for the first four cycles of my standard of care V + O treatment. As part of that 4-month trial I agreed to an “extra” CT scan and BMB (this will be my fourth) both of which I’ll get in a few weeks. Now I’m wondering if this BMB will include the deep MRD testing. I assumed it would but maybe I’m incorrect? This is a question I’ll be asking at my next doctor’s appointment.

Thank you,

Mark

[SeymourB in reply to HopeME]

Mark -

There are now 3 options for MRD testing. I see different notations used.

The original uses a 10,000 cell sample of CLL cells, and is done via flow cytometry. Sone call it 10K or MRD4 (10 to the 4th power is 10K).

There's also high sensitivity flow cytometry which can see 1 cell in 100K, MRD5 (10 to the fifth).

Then there's ClonoSEQ, plus there are other DNA based sequencing tests that individual research labs do. I thought I saw an independent competitor to ClonoSEQ, too.

cllsociety.wpengine.com/tre...

So other than the 10K, it's not all standardized yet, but more and more studies are doing some kind of MRD. I found this article useful:

nature.com/articles/s41375-...

I'm a nerd. I did 23andMe a decade ago, and have been looking at whether whole genome sequencing of normal cells might be useful soon. So far, most doctors can barely cope with keeping up with new tests. I'm already robbing my 401K retirement, so I might pay out of pocket for ClonoSEQ if insurance or the study doesn't cover it. I can't say it will prevent a wrong decision, though.

=seymour=

[Indolent]

Good luck Seymour. I hope the screening goes well and that you don't hit any snags getting qualified for the trial.

[LeoPa]

That looks like a lot to chew on. Good luck with the trial!

[DinosaurDad]

Best of luck! I'm on venetoclax plus Obinituzumab, 6 months in. Seems to be working well. The protocol for your trial demonstrates the latest thinking about combos...hope you (and me!) Get to those deep remission. It'll be time consuming on startup, but just hang in there.

[SeymourB in reply to DinosaurDad]

DinosaurDad -

I don't know how insurance companies and national health systems will react to triplet therapies. The therapies have to show both better effectiveness, and overall lower cost, I think. It's easy to beat lifetime ibrutinib, but might not be so easy to beat fixed duration V&O or fixed duration monotherapies for cost.

I think they need to do these trials because it's an obvious thing to do, and to try to put the argument to rest

=seymour=

[DinosaurDad in reply to SeymourB]

Great point. The other key question is how you sequence...hopefully everyone gets a long remission but then, if you relapse, what's next? Will take time to sort out.

[SeymourB in reply to DinosaurDad]

DinosaurDad -

This is why I want ClonoSEQ and the additional testing that MDA does - to see which clones survive, and which mutations have survived.

Since Pirtobrutinib is non-covalent, the usual C481S mutation that covalent BTKi's (ibrutinib, acalabrutinib, zanubrutinb) develop will probably not appear. So, Zanubrutinib would still be an option, I believe.

Venetoclax resistance mutations are a bit trickier to predict, from what I have gleaned so far. But I think they can test for them.

=seymour=

[DinosaurDad in reply to SeymourB]

Wow clearly you're well informed and on top of all this. And you have the advantage of working with a premier CLL center - I read and watch any communications they produce about CLL and new treatments. So you're in great hands. I'm actually in a trial as well, at my center (Sloan Kettering in NYC). They'll be testing for UMRD starting at 6 months...if the CLL level passes the test, I'll go off treatment as early as 9 months. The idea of the trial is the belief that if you've reached that low level, you can actually stop treatment before the normal length of the protocol (and save some of the toxicity etc. of continuing on the meds).

[SeymourB in reply to DinosaurDad]

DinosaurDad -

I only look well informed! I have so many questions, the list is too long, and I have to prioritize what to ask, and what to try to look up myself. And I can certainly make wrong assumptions at times.

I must say that now that treatment is near, I read treatment related things with new eyes.

=seymour=

[Phil4-13]

SeymourB, 💪May your participation have the most successful results ever seen at MDA! 🙂Sandra

[Dahlia7]

Sounds promising to me. Dr Thompson was my doctor and I thought he was great. LOXO used Colpitts for reimbursement when I was on pirtobrutnib. They were incredibly nice to work with. Please ask about it. They covered my expenses. Good luck. Tony

[Stamphappy]

Seymour, thank you so very much for posting your genetics and your hopeful participation in this trial.. I am an unmutated trisomy 12 also but with 13q deletion also. I will be following you with great interest.I think it's only natural to anticipate the worst. That's OK as long as you "plan for the worst" BUT FOCUS ON THE BEST POSSIBLE OUTCOME. Think positively, Seymour. We are all here for you! I enjoy your comments. I look forward to your updates and pray for acceptance into the trial, God's presence to guide you and your family, and an amazing response to treatment.

[SeymourB]

Stamphappy -

Planning for the worst is so pessimistic! Pick the coffin, and call the brothers home! My anxiety can picture so many dire situations of multiple cancers, auto accidents, tornadoes and hurricanes.

I think the big thing is where possible, to try to have a plan that's a little better than, "we'll cross that bridge if we come to it." So I'm looking for possible bridges.

One bridge has to do with neutropenia and sepsis, which would put me in the hospital here in New Orleans. The chance for that is probably higher than in regular V&O. I'm trying to make sure that everyone at MDA knows that I'm from out of town, and that they need to communicate to my doctors here. Most of the time, I've found it's better for me or my doctor to initiate the call to MDA instead of vice versa. So we'll be giving a couple of MDA on-call phone numbers to the emergency room or ambulance driver.

I had a scare in December when the new MDA oncologist saw 65% abnormal lymphocytes in my differential, and was worried about a Richter's or other transformation. Yes, it can happen in Watch and Wait. He wanted a flow cytometry done to investigate, and I asked him to call my local hemo/onco to have them order it - and that worked, that time.

And there's also financial toxicity. I also had a problem explaining to MDA that my insurance covers MDA at an Out Of Network rate (60% - I have a 40% copay). The MDA financial lady said they normally only check for any insurance reimbursement at all - not the rate. So she'll investigate that, and I asked her to ask the insurance for an Out of Network Exception, which would bill insurance at 80% (me paying 20%). The insurance nurse also told me that my insurance has a specific clause for clinical trials, but I can't seem to find it on their website yet.

=seymour=

[Stamphappy]

The financial cost burden is so immense for all types of cancer. It should be enough for the universe that our emotional burden is beyond compare? 💔 Those who exorbitantly profit from our despair will surely answer to the Man upstairs. I thank Him that we have this wonderful group and the dedicated souls who strive to create a cure. ❤️ I wish I had the words to comfort you, Seymour. I'm told trial participation may ease some of the cost burden. Another really important point here is, I believe, as a study participant, you will be more closely monitored. It is in their best interest, afterall, that your treatment be a success! Hopefully, that knowledge will help ease some of your anxiety. All my best to you, Seymour.

[Cave123]

Thanks for sharing SeymourB. Road trips can fun, and as you know Pirtobrutinib is sounding very promising - best of luck and keep us posted, stay well CAVE