Phase 2 study of MRD driven time limited therapy with Zanubrutinib, Obintuzumab and Venetoclax (BOV) in untreated patients.

[Jm954]

These are initial results, published as an abstract in May 2020

Zanubrutinib (B) is a highly specific BTK inhibitor that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with O+Ven. They hypothesized that treatment with BOVen using a MRD driven discontinuation strategy can achieve frequent uMRD and durable responses.

Aims: To determine the rate of uMRD response. To determine the time to uMRD response. To determine the proportion of patients who successfully discontinue therapy.

The study accrued 39 pts, median age was 59 years (23-73), there was a 3:1 male predominance, 67% had CLL IPI high or very high risk, 72% had unmutated IGHV, and 10% had 17p del and/or TP53 mutated. All patients were evaluable for toxicity with 37 evaluable for efficacy.

Treatment duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood by flow cytometry, sensitivity >10-4) starting cycle 7 day 1 (C7D1). then every 2 cycles. Once PB-uMRD was determined and confirmed in bone marrow, patients completed 2 additional cycles then discontinued therapy.

At a median follow up of 9 months (mo; 3-12+), 26/37 (70%) pts achieved PB-uMRD and 23/37 (62%) pts achieved BM-uMRD. The median time to PB-uMRD was 6 mo (4-10+). Of 26 with PB-uMRD, 23 had BM-uMRD with 15/23 completing 2 additional cycles and discontinued. Two pts had detectable BM-MRD, and 1 pt with PB-uMRD awaits BM. The frequency of pts achieving objective and complete responses were 97% (36/37) and 27% (10/37).

The most common treatment emergent AEs were neutropenia (49%), infusion related reaction (41%), bruising (41%), diarrhea (39%) and thrombocytopenia (36%). Grade ≥3 AEs occurring in ≥5% pts were neutropenia (15%), thrombocytopenia (5%) and pneumonia (5%).

Conclusion: BOVen is well tolerated and achieves rapid uMRD: 70% PB-uMRD and 62% BM-uMRD with limited follow-up (to be updated on presentation). Fifteen (41%) had confirmation of the prespecified uMRD endpoint and are in follow-up off therapy per protocol. The value of MRD-directed treatment duration will be evaluated with continued follow up.

library.ehaweb.org/eha/2020...

Jackie

[Canuck901]

another triplet success, this one knocked it out of the ballpark and even took on the very high risk category which many do not .

amazing results

hopefully it gets rapid approvals!

[Jm954 Administrator in reply to Canuck901]

I agree and I hope they repeat this with larger numbers of patients, enough to power it for all the patient groups, not just a select few.

Jackie

[Canuck901 in reply to Jm954]

agreed and wow 67% of the patients were high to very high risk group. to achieve those results outstanding.

more competition on the horizon , i assume the phase 3 trial will be much larger

[SofiaDeo in reply to Canuck901]

"High to very high risk" that was not including a large percentage of 17p del patients, that was 10% overall. So non-17p "high risk".

[Smith123456]

all these 'trials' venetoclax is still the 'heavy lifter'. i'd be more encoraged by great 'trials' without it

[SofiaDeo in reply to Smith123456]

Well, if the other meds can reduce the TLS risk seen with Venclexta, and prevent resistance, I think they are useful. Many people have comorbidities where electrolyte imbalances and/or renal or liver issues make V monotherapy stressors risky. And if we are seeing remissions/uMRD that lasts several years longer than otherwise, it's worthwhile I bet.

When I did my first Campath treatment that put me in almost 5 year remission, I was on that 16 weeks. A 12 week treatment years later had remission lasting only 1 year.

Remember, in other disease states it is common to do multi drugs at lower doses to get a therapeutic response with lower side effects. I am grateful to all the people willing to do these trials, finding out if the various combos are effective!

[Smith123456 in reply to SofiaDeo]

Not my point. there are a bunch of btk inhibitors. there are a bunch of cd20 drugs. Only one bcl2 drug-which happens to be the main powerhouse

[SofiaDeo in reply to Smith123456]

Ahhhh, I get it. Yes, more BCL-2 type inhibitors would be great! I wonder if the pandemic has contributed to trials involving meds that the companies can bill insurance for, as opposed to a new drug they have to provide for free.....

[newyork8 in reply to SofiaDeo]

Ah...another drug companies are greedy evil people post. I guess drug companies should not develop drugs they can charge for. So who pays the researchers? They would go bankrupt. News flash...drugs are developed to make profit. Does your profession work for free? And btw the taxpayers funded much of this vaccine development. So really none of this is free or ever can be free. Thank goodness for big pharma. I'd be dead without them. May I suggest you buy shares in these companies so you can share both medically and financially in their success.

[Jm954 Administrator in reply to newyork8]

I'm not sure I read that into either SofiaDeo or Smith123456 's replies but you're right in that, without the financial incentive none of these drugs would be developed.

[newyork8 in reply to Jm954]

I suppose I"m too sensitive to the issue so I apologize if I misinterpreted. Pharma is often bashed as an evil money grubbing industry. I agree drug prices are outrageously high but the alternative appears to be a world with not as much innovation. The government does fund a large amount of research on taxpayer funding.

[Big_Dee in reply to newyork8]

Hello newyork8

Yes money is the driver. The USA develops more new drugs per year than the rest of the world combined. This is a good thing. I for one am happy to see the BOV test results, not just for chance to be lower reoccurring costs, but not having to live with adverse side effects all ones life. Blessings.

[Jm954 Administrator in reply to Smith123456]

Why? The point of these combination therapies is the synergy between the drugs, not just the Venetoclax element.

It takes longer with a BTKi to achieve remission and I'm not talking about uMRD but the remissions do improve over time.

There is some evidence emerging that the fixed duration therapies comprising of Ven+CD20 are not providing remissions as long as the BTKi s, particularly for the p17del and TP53 mutated patients.

Jackie

[Canuck901 in reply to Jm954]

that’s not good, so the obinituzimab pkus Venetoclax or the Rituximab plus venetoclax are not giving long enough remission ? compared to let’s

say Zanubrutnib plus venetoclax?

[Jm954 Administrator in reply to Canuck901]

It's early days yet, remember this takes years to tease out of the data, but it looks like the curves for V+O are starting to separate. They may come back together again, we need to wait and see.

[Smith123456 in reply to Jm954]

my original point was that it would make me feel better about the future IF there were more bcl-2 drugs. Venclexta always seems to be in the combos-because it's the most important of the 3 classes

[SofiaDeo in reply to Smith123456]

As Smith123456 said, it would be nice to start seeing more bcl-2 drugs, as well as other mechanisms of action. And newyork8, apologies if it sounded like I was bashing Big Pharma, that wasn't my intent. The pandemic has caused financial upheaval, and I merely wondered to what extent this impacted the ability to explore any newer option, since it represents a significant up-front investment. Many businesses have been hit hard, research trials have been put on hold due to financial or staffing constraints. Attention has been (rightly) focused on R&D to stop or mitigate Covid effects. I agree being financially solvent is the bottom line for any going concern, whether a major university center, non-profit as well as for-profit, in addition to our docs and the drug companies.

[Jm954 Administrator in reply to Smith123456]

I disagree that it's the most important. It's always there as it's the only one in its class. There's always a BTKi too and as I said, its the synergy in how they work that's important. However, I do agree it would be good to see some new biosimilars to Venetoclax if only to provide some competition.

[SeymourB]

Here's a full paper on BOVen:

ncbi.nlm.nih.gov/pmc/articl...

Time‐Limited Triplet Therapy Induces Rapid Undetectable MRD Responses in CLL

Here's the clinical trial info - still recruiting - Memorial Sloan Kettering:

clinicaltrials.gov/ct2/show...

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

[Smakwater]

Looking better, however, what's with the 49% neutropenia with grade ≥3 being ≥5%?

Not sure I am perceiving this accurately

JM

[AussieNeil Partner Administrator in reply to Smakwater]

49% of patients experienced some degree of neutropenia. The percentage experiencing grade 3 (under 1.0) or grade 4, under 0.5 is much less as you would expect.

[Smakwater in reply to AussieNeil]

Thanks for that Neil.

I was interpreting it backwards thinking it meant grade 3's were greater than 5% which wasn't making sense.

Reading tech info late at night is not always productive.

JM

[wroxham-gb]

Thanks Jackie.

Sue

[Awksom]

I am one of the original 37 on the BOVEN clinical trial at Sloan Kettering. People at Sloan have been top notch . Here is my quick update for those interested.

>My background is diagnosed as SLL February 2016. On WW until September 2019. 13q deleted, un-mutated. Had two incidents of AIHA and was treated with (blood transfusion in first case and) prednisone ( A devil drug in my opinion due to its side effects if taken longer term).

>I started the BOVEN trial with Zanubrutinib tabs 160 mg BID in 9/2019 with no negative reactions.

>At the same time I initially did a ramp up over two days for the Obinutuzmab which was successful leading to 2 more infusions at a step up pace. I finished that drug regimen with no issues.

>My nodes, biggest were in the groin area and armpits with smaller ones in the neck , were gone quite quickly. Spleen down to "normal" size. Fatigue was largely gone although I still felt tired (a distinction between "fatigue" and "being tired" that CLL patients will understand). At that stage blood work looked good with elevated WBC and ALC first increasing and then falling back down into the upper ends of normal rage. Platelets were above 100 which was good for me since those counts are usually low for me.

>Venetoclax was introduced via a five week ramp-up from 20mg to 400mg. Depending on your risk level you are either hospitalized during the ramp ups or, hopefully, can do them as an out patient. In my case I had to have potassium and magnesium administered a few times. Otherwise, the Venetoclax simply brought all back to normal. Except for platelets all came back within acceptable range and have stayed there since. Issue at that point was very dry skin and continued easy bruising and easy cuts.

>Things went swimmingly until about Cycle 10 when I developed severe diarrhea. Was eventually cut back on half dosage of both the Zanubrutinib and Venetoclax, and lost 15 lbs. in 6 weeks. The drug cutback helped tremendously (and the loss of weight was a benefit in my case) . I carried on with half dosage until completion of the drug segment of the trial through Cycle 14 (10/2020).

>I reached blood FLOW uMRD at Cycle 8 (4/2020) and Bone Marrow uMRD at Cycle 12 (9/2020). Throughout the process my CT's were progressively better each time.

>Since the end of the drug part of the trial my two FLOW's have shown uMRD. I have FLOW blood work done every three months and CT scans every 6 months under the trial protocols.

> The only significant issue post drugs is that I developed shingles, a somewhat painful dose of it. Was put on anti-viral to combat it as well as another smaller dose to prevent resurgence. Still feel tired but that may be due to the acyclovir for shingles, latent effect of the drug regime and/or just age.

>Given that the drugs basically killed off my B Cells, a COVID 19 vaccine is of no use at this time. Hopefully I can get one by August or so.

That's the story so far. Hope it is of interest,

Best to all in your own SLL/CLL adventures.

[Jm954 Administrator in reply to Awksom]

That's a great report, so glad it worked so well for you. Tough to get shingles though

Thanks for responding.

[Awksom in reply to Jm954]

Get the shingles shot if you dont already have and the doc says ok. Shingles is painful for sure.

[SofiaDeo in reply to Awksom]

If you are able, you can see if valacyclovir works better for shingles prevention & causes less fatigue. I prefer it because prophylaxis is only once daily and treatment 2-3 times daily. My main issue with 1 gm valacyclovir is that it's a horse pill & makes me nauseous if I don't drink enough water. But any med makes me nauseous, and I prefer "less times a day" than "smaller thing to swallow."

[Awksom in reply to SofiaDeo]

I was on valacyclovir for a week, horse pills for sure, 1GM 3x day for a week then acyclovir 400mg 2x day as a preventative. From what I am told many that get shingles after cancer treatment get a repeat of the shingles when their B cells are low.

[SofiaDeo in reply to Awksom]

Yup it can be true. Whenever our immune system gets too compromised, the shingles or oral version can pop out. I average a breakout of some sort yearly, and they are not as bad as my first one with the preventative treatments & immediately switching to treatment dose. This sounds odd, but I kind of like that I prodrome before breakouts, or prodrome & know to increase preventative dose to treatment dose & possibly stop a breakout. I know my immunity is definitely low just then & to be especially careful of other infections. I've managed to avoid hospitalization for any infections, just treated as an outpatient.