Clinical Trial Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab Untreated CLL & SLL @EU & UK locations

[lankisterguy]

A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Phase 3- Radomized Open Label

clinicaltrials.gov/ct2/show...

Locations

United States, California

University of California San Diego Medical CenterNot yet recruiting

La Jolla, California, United States, 92093

United States, Georgia

Winship Cancer Institute of Emory UniversityNot yet recruiting

Atlanta, Georgia, United States, 30322

United States, Kentucky

Norton Cancer InstituteNot yet recruiting

Louisville, Kentucky, United States, 40207

United States, New Jersey

John Theurer Cancer CenterNot yet recruiting

Hackensack, New Jersey, United States, 07601

United States, Washington

Swedish Cancer InstituteNot yet recruiting

Seattle, Washington, United States, 98104

Belgium

ZNA StuivenbergRecruiting

Antwerpen, Belgium, 2060

Institut - Jules BordetRecruiting

Brussel, Belgium, 1000

UZ GentRecruiting

Gent, Belgium, 9000

Virga Jessa ZiekenhuisRecruiting

Hasselt, Belgium, 3500

UZ Leuven GasthuisbergRecruiting

Leuven, Belgium, 3000

Canada, Alberta

Tom Baker Cancer CentreRecruiting

Calgary, Alberta, Canada, T2N 4N2

Cross Cancer InstituteRecruiting

Edmonton, Alberta, Canada, T6G 1Z2

Canada, Ontario

Juravinski Cancer CentreRecruiting

Hamilton, Ontario, Canada, L8V 5C2

The Ottawa Hospital - General CampusRecruiting

Ottawa, Ontario, Canada, K1H 8L6

Canada, Quebec

CIUSSS de l'Est-de-l'Île-de-Montréal Installation Hôpital Maisonneuve-RosemontRecruiting

Montreal, Quebec, Canada, H1T 2M4

Jewish General HospitalRecruiting

Montreal, Quebec, Canada, H3T 1E2

Czechia

Fakultni nemocnice Brno, Interni hematologicka a onkologicka klinikaRecruiting

Brno, Czechia, 625 00

Fakultni nemocnice Hradec KraloveRecruiting

Hradec Kralove, Czechia, 500 05

Fakultni nemocnice OstravaRecruiting

Ostrava, Czechia, 708 52

Fakultni nemocnice Plzen, Hemato-onkologicke oddeleniRecruiting

Plzen, Czechia, 304 60

Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologieRecruiting

Praha 2, Czechia, 128 08

Denmark

Aalborg University HospitalRecruiting

Aalborg, Denmark, 9000

Aarhus UniversitetshospitalNot yet recruiting

Aarhus, Denmark, 8200

Rigshospitalet Copenhagen University HospitalRecruiting

Copenhagen, Denmark, 2100

Herlev HospitalRecruiting

Herlev, Denmark, 2730

Odense UniversitetshospitalNot yet recruiting

Odense C, Denmark, 5000

Roskilde SygehusRecruiting

Roskilde, Denmark, DK- 4000

France

CHU de Clermont-FerrandRecruiting

Clermont Ferrand, France, 63000

Hopital Claude HuriezNot yet recruiting

Lille, France, 59037

CHU MontpellierRecruiting

Montpellier, France, 34295

Hopital Haut Leveque Service Maladie Du SangRecruiting

Pessac, France, 33604

Centre Hospitalier Universitaire de Reims, Hôpital Robert DebréRecruiting

Reims, France, 51100

Institut Universitaire du Cancer Toulouse OncopoleRecruiting

Toulouse Cedex 9, France, 31059

CHU BretonneauRecruiting

Tours Cedex 9, France, 37044

CHU-NancyRecruiting

Vandoeuvre Les Nancy, France, 54511

Institut Gustave RoussyRecruiting

Villejuif, France, 94805

Israel

Bnai Zion Medical CenterRecruiting

Haifa, Israel, 31048

Carmel Medical CenterRecruiting

Haifa, Israel, 34362

Hadassah Medical CenterRecruiting

Jerusalem, Israel, 9112001

Western Galilee Medical CenterRecruiting

Nahariya, Israel, 22100

Sheba Medical CenterRecruiting

Ramat Gan, Israel, 52621

Tel Aviv Sourasky Medical CenterRecruiting

Tel Aviv, Israel, 64239

Netherlands

FlevoziekenhuisRecruiting

Almere, Netherlands, 1315RA

OLVGNot yet recruiting

Amsterdam, Netherlands, 1091AC

Academic Medical CenterRecruiting

Amsterdam, Netherlands, 1105 AZ

Reinier de Graaf GasthuisRecruiting

Delft, Netherlands, 2625 AD

MC HaaglandenRecruiting

Den Haag, Netherlands, 2512 VA

Albert Schweitzer ZiekenhuisRecruiting

Dordrecht, Netherlands, 3318 AT

CatharinaziekenhuisRecruiting

Eindhoven, Netherlands, 5623 EJ

Spaarne GasthuisRecruiting

Hoofddorp, Netherlands, 2134 TM

Zuyderland Medical CenterRecruiting

Sittard-Geleen, Netherlands, 6162 BG

Antonius hospitalRecruiting

Sneek, Netherlands, 8601 ZK

Elisabeth zkhRecruiting

Tilburg, Netherlands, 5022 GC

Poland

Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali MiejskichRecruiting

Chorzów, Poland, 41-500

Uniwersyteckie Centrum KliniczneWithdrawn

Gdansk, Poland, 80-952

Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w LodziRecruiting

Lodz, Poland, 93-510

Samodzielny Publiczny Szpital Kliniczny Nr 1Recruiting

Lublin, Poland, 20-081

Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka,Recruiting

Slupsk, Poland, 76-200

Instytut Hematologii i TransfuzjologiiRecruiting

Warszawa, Poland, 02-776

Klinika Hematologii, Nowotworow Krwi i Transplantacji Szpiku SPSK nr 1Withdrawn

Wroclaw, Poland, 50-367

Russian Federation

Clinical Oncology Center of TatarstanWithdrawn

Kazan, Russian Federation, 420029

S.P. Botkin Moscow City Clinical HospitalRecruiting

Moscow, Russian Federation, 125284

Nizhniy Novgorod Region Clinical HospitalRecruiting

Nizhny Novgorod, Russian Federation, 603126

Ryazan Regional Clinical HospitalRecruiting

Ryazan, Russian Federation, 390039

FSBIFederal Centre of Heart, Blood and Endocrinology named after V.A.Almazov MoH of the RFRecruiting

Saint Petersburg, Russian Federation, 197341

St.-Petersburg Clinical Research Institute of Hematology and TransfusiologyRecruiting

St. Petersburg, Russian Federation, 193024

Spain

Hosp. Univ. Vall D HebronRecruiting

Barcelona, Spain, 08035

Hosp. Clinic I Provincial de BarcelonaRecruiting

Barcelona, Spain, 08036

Hosp. de La Santa Creu I Sant PauNot yet recruiting

Barcelona, Spain, 8041

Hosp. Univ. de La PrincesaRecruiting

Madrid, Spain, 28006

Hosp. Gral. Univ. Gregorio MaranonRecruiting

Madrid, Spain, 28007

Hosp. Univ. Infanta LeonorRecruiting

Madrid, Spain, 28031

Hospital Ramon y CajalRecruiting

Madrid, Spain, 28034

Hosp. Univ. Fund. Jimenez DiazRecruiting

Madrid, Spain, 28040

Clinica Univ. de NavarraRecruiting

Pamplona, Spain, 31008

Hospital Clinico Universitario SalamancaRecruiting

Salamanca, Spain, 37007

Hosp. Virgen Del RocioRecruiting

Sevilla, Spain, 41013

Sweden

Sunderby Sjukhus MedicinklinikenRecruiting

Luelå, Sweden, 97180

Skånes universitetssjukhusWithdrawn

Lund, Sweden, 22185

Karolinska Universitetssjukhuset Solna, Centrum för Hematologi, StockholmNot yet recruiting

Stockholm, Sweden, 171 76

Turkey

Gazi Universitesi Tip FalKultesiRecruiting

Ankara, Turkey, 06500

Ankara Universitesi Tip Fakültesi İbn-i Sina HastanesiRecruiting

Ankara, Turkey, 06590

Ondokuz Mayis Universitesi Tip FakultesiRecruiting

Atakum, Turkey, 55270

V.K.V. Amerikan HastanesiRecruiting

Istanbul, Turkey, 34365

Dokuz Eylul Universitesi Tip FakultesiRecruiting

Izmir, Turkey, 35340

United Kingdom

Birmingham Heartlands HospitalRecruiting

Birmingham, United Kingdom, B9 5ST

Royal Bournemouth HospitalWithdrawn

Bournemouth, United Kingdom, BH7 7DW

Addenbrookes HospitalRecruiting

Cambridge, United Kingdom, CB2 0QQ

Queen Mary University of LondonRecruiting

Charterhouse Square, United Kingdom, EC1M 6BQ

New Victoria HospitalRecruiting

Glasgow, United Kingdom, G42 9LF

St James's HospitalRecruiting

Leeds, United Kingdom, LS9 7T

Derriford HospitalRecruiting

Plymouth, United Kingdom, PL6 8DH

Barking Havering and Redbridge University Hospitals NHS TrustRecruiting

Romford, United Kingdom, RM7 0AG

Royal Hallamshire HospitalRecruiting

Sheffield, United Kingdom, S10 2JF

[AdrianUK]

Thanks for sharing. This is an interesting study. But please note that if you look at the inclusion criteria it is ONLY for people who are not healthy enough to undergo FCR and that is judged quite specifically. So don’t think of this as competing for patients for FLAIR as by definition you’d have to be ineligible for flair to be enrolled in this. But when I was having heart screening as they were worried about my tachycardia and we were thinking of treatment I looked into this trial in case I turned out to have a significant heart issue that would have ruled me out of FLAIR.

[MsLockYourPosts Passed Volunteer]

Interesting! I am a big believer in obinituzumab, but got it without chlorambucil. I would think more than twice about any phase lll trial that includes chlorambucil as a comparator. This, like other trials in the past, appears to be set up to get the other combination approved. Just my opinion.

[AdrianUK in reply to MsLockYourPosts]

Hi, one issue is often with regulators and what they will allow as the comparator for a trial to get a license. Bearing in mind this is a group of people not well enough for FCR I guess Chlorambucil is not totally out of the question as a treatment? It’s still mentioned in guidelines if I remember correctly.

[MsLockYourPosts Passed Volunteer in reply to AdrianUK]

I understand that. Many have questioned the set up of phase three trials. Yes, Chlorambucil is still out there. The Gazyva trial compared Chlorambucil alone vs Gazyva plus chlorambucil, for example. Clearly the set up was to get Gazyva approved, and now that it is, many doctors leave it out or advise patients to "lose the chlorambucil" to avoid the toxicity. It's time to set up realistic trials that give real answers. Many are fighting for that.

[AdrianUK in reply to MsLockYourPosts]

There are issues around trials that are very complex. Clearly with cll we couldn’t do placebo controlled trials unless perhaps in patients who don’t really need treatment and even then that wouldn’t be great ethically. So then it’s no wonder that the idea is to take a background treatment and randomize to that alone or that plus something. Or to compare two treatments. Our current first line treatments are so good that you could never easily show that a new drug is better than them. If 80-90% are responding then how do you show your new drug is better than that. Of course it might go deeper and last longer but then the trials will take too long. So it makes sense to go for a sick population or a second line population. Perhaps we should be insisting on more post marketing trials like FLAIR. So take Venetoclax for example. It works so well in third line that after giving it a third line license you do the first line combo trial and for that matter they also did the second line VR combo trial.

There’s an issue around numbers of patients needed for some of these kind of trials too.

Would you be willing for example to forgo ibrutinib or FCR firstline and take something completely unproven? I wouldn’t.

Remember also that we need to learn how to use drugs. When venetoclax was used initially it was killing people due to tumor lysis. As tragic as that was it is better that happened to people who were at the end of the then available options than someone taking their first treatment. Those folks gave their lives so that doctors could realize they needed to titrate more slowly for those of us who end up using it today.

The needs of regulators, pharma companies, doctors, and patients don’t always completely align with trial design.

[AdrianUK in reply to AdrianUK]

Final point. There is a theory that with any CD20 antibody if it is given alone without any other cytotoxic agent then all it will do is create a huge selection pressure for the cells to evolve and drop their CD20 antigens. This is presumably why the company and regulators agreed to to for that combination for the license. And of course now the study is really about seeing whether that combo is as good as the new kid on the block for sicker patients v+I. Personally I’d be quite happy to be in that trial if i was eligible and had looked into it a bit a couple of months ago.

[MsLockYourPosts Passed Volunteer in reply to AdrianUK]

Rituxan alone gave me 10 years. Gazyva alone has given me me a very strong remission. A lot has been written about flaws in many trial protocols., and has been noted as a reason that so many are having trouble recruiting. No mention was made of placebo involved trials.

As for the venetoclax trial, one of the two deaths was a friend, after they upped his dosage beyond what was reasonable, rather than ramping it up. The company was taken to task at the next ASH conference for their lack of responsibility - very unusual, but totally justified! If these companies want trial participants, they need to setup reasonable and responsible trials! There are some very good ones, especially some of the phase two trials, but there are also trials designed just to get a drug approved.

[AdrianUK in reply to MsLockYourPosts]

Interesting to hear that rituxan gave you ten years. I guess it shows that the theory doesn’t always work in practice. And we will never know of course if FCR would have given you 20 or more.

I guess I mentioned placebo because if you want to show a drug works then the cheapest (and way to expose as few people as possible to the drug) is the good old fashioned placebo controlled trial. But we can’t do that in a condition like ours.

So then we have to have a comparator.

And if you can’t to a placebo controlled trial doing a standard drug plus yours vs standard drug alone is a good alternative.

To compare two dug regimes which you expect to work really well and to show equivalence or a small benefit to your new one takes a HUGE and long study.

I’m not surprised they go for the study designs they do. Chlorambucil is well tolerated but not as strong as some of the other chemo. Give it with a newer drug and it could be a great combo (and vs alone it will be easier to prove the combo is better). And it’s not like Chlorambucil alone isn’t considered an option for treating patients who can’t tolerate FCR.

I know there’s two schools of thought in treatment at the moment. Sequential monotherapy vs hit it hard with combos. I rather suspect the combos will work out best in the end. But that’s for theoretical reasons as opposed to loads of evidence since it’s much harder for a cell to develop resistance to two treatments at once and so any that develop resistance to one of the things you are giving would get mopped up by the other.

As for your friend I am certainly sorry to hear that. Must have been Very difficult for you to have gone through that and to have realized that the dose was ramped up too quickly.

Those of us who have recently been diagnosed and are embarking on our treatment journeys don’t realize just how much we owe to those who have gone before and how much more fortunate we are than people treated even just a few years ago regarding the availability of newer drugs.

The pharma industry is not perfect. But without it we wouldn’t have any of the treatments we currently enjoy. And so far nobody has come up with a better way of getting new drugs to the market. In theory there’s nothing stopping universities or the NHS etc creating and studying new drugs. But only the profit motive and the funds involved seem to be able to push these things over the line. It’s really an example of capitalism at work. Seems very selfish and yet if it works well capitalism turns rich people’s greed round for the greater good of us all.

What was it Churchill said of democracy? Perhaps it could be also said of the idea of commercial companies funding the creation of drugs “the worst system ever created except any other that has ever been tried”

[Cllcanada Top Poster CURE Hero in reply to AdrianUK]

There have been a number of placebo trials in CLL, often in the maintenance of post-treatment disease.

Chlorambucil has finally been replaced with Chlorambucil with Gazyva (obinutuzumab) for most pivotal drug approval trials, particularly first line.

Without the Orphan Drug Act there would be no CLL drugs. It is the patent protection, huge tax incentives, free research, government supported clinical trials, that allow drug companies to see a financial opportunity. EU has a similar but less robust system...

CLL drugs are now being developed in China, Korea, Japan, Australia, Germany, France, the U.K., India, Russia and so on.. it's global...many come from academic research efforts as well.

~chris

[AdrianUK in reply to Cllcanada]

Chris been thinking about what I’d do if I was looking after a new CLL drug and trying to get it to market as quickly as possible.

What do you think of this idea.

There’s a load of people out there on Ibrutinib and who have got some benefit from it but not MRD negative status.

If we take the premise that after a certain amount of time in MRD negativity it may be reasonable to stop treatment how about this for a design?

1. Enroll patients on ibrutinib who have a benefit but no MRD negativity. You could even define what level of measurable disease you wanted as a minimum.

2. Randomize to continued Ibrutinib plus placebo (and remember outside of the trial they would continue Ibrutinib monotherapy in these circumstances) vs Ibrutinib plus the new drug.

3. Make the primary end point reaching MRD negativity. Apply for a license on this basis (not sure if regulators would accept this by the way just an idea at the moment)

4. Once met MRD negativity after a certain point of time re randomize to stop all meds vs continue combination vs stopping Ibrutinib (NB anyone on ibrutinib who met MRD negativity would be allowed to continue into this phase too) new primary endpoint becomes progression free survival. Note if there was no difference this wouldn’t affect the acute license as it would show your new drug could get Ibrutinib patients to a point they could stop.

5. For placebo patients after x months you could have a still blinded crossover to the new drug if they hadn’t responded. In fact this could take place in some patients at six months and others at nine say in order to maintain the blind and demonstrate the effectiveness in this group also.

The problem with all clinical research for regulatory submission (something I’ve spent much of my career working in) is that the transitional design in any disease area is almost impossible to supplant and replace.

So as I say this is just offered as a thought experiment.

4.

[Cllcanada Top Poster CURE Hero in reply to AdrianUK]

The FDA is looking at this.... just today

fda.gov/NewsEvents/Newsroom...

[MsLockYourPosts Passed Volunteer in reply to AdrianUK]

FCR would probably have killed me. Chlorambucil almost did. My case is vert atypical. Thank goodness for a team of specialists who came up with an approach that worked for me.

[AdrianUK in reply to MsLockYourPosts]

Well this is the thing isn’t it. We always have to be mindful of the need of INDIVIDUAL patients to be treated by their doctors according to their own situation. Did you have co morbidity at the time? Must say this morning I feel like FCR IS killing me. But that feeling is tempered by knowing the huge reduction in my White count after just 24 hours on treatment. At least I know my cells are chemo sensitive. Let’s hope they stay that way.

[MsLockYourPosts Passed Volunteer in reply to AdrianUK]

No, just a very atypical case.

[AdrianUK in reply to MsLockYourPosts]

What was atypical about you.

[MsLockYourPosts Passed Volunteer in reply to AdrianUK]

Adrian , my story is all over the site. People don’t need to read it over and over here. Suffice it to say that there are only two very small studies internationally about my situation and no trials.

[roszika]

Why I am upset. Great that this trial kis happening but it seems nowhere is it happening here for us Australians with CLL

[Cllcanada Top Poster CURE Hero in reply to roszika]

This trial is running in many locations in Australia...

A Study Comparing BGB-3111 With Bendamustine Plus Rituximab in Patients With Previously Untreated CLL or SLL

clinicaltrials.gov/ct2/show...

BGB-3111 is now called Zanubrutinib...

~chris

[roszika in reply to Cllcanada]

Thanks Cllcanada. I probably am no aware because I am not up the level with CLL that requires a trial. My specialist probably knows about these. It was only that I did not see Australia listed. Anyway thanks, you are a wealth of information