Phase 1 Trials and My Advice on How to Survive and Be Your Own Best Advocate with CLL (chronic lymphocytic leukemia)

 Friends,

This week we have published helpful information from two patients on the CLL Society website.

The first is a thoughtful well-referenced editorial by Cynthia Havstad on the personal value of enrolling in a Phase 1 trial

Cynthia recently enrolled in a trial of a novel antibody directed against ROR1. This promising and very specific target is the culmination of decades of works by Dr. Kipps and his team at UCSD. For the background on why therapies directed against ROR1 are so exciting and details the trial, click here to watch my interview with Dr. Kipps. The link to the actual trial is found here.

To read Cynthia's helpful own story about her experience in considering a trial so early in a new drug's development and her actual experience please click here.

Without researchers such as Dr. Kipps and brave and smart patients such as Cynthia, we would not be making the amazing progress that we are in treating CLL.

The second patient we present this week is yours truly sharing my full 24 minute video from the CRC 2015 conference. My topic was pretty fundamental: Being our Own Advocate and Staying Alive with CLL (chronic lymphocytic leukemia).

It's a dense presentation.

First I briefly share my own 10-year history with CLL.

Self advocacy's risk (yes there are risks) and benefits are outlined.

Next I catalogue my advice in term of my personal three steps for mindful survival.

1. PREPARE
2. ACT 
3. BE AWARE

I tried to keep my counsel very practical and even a little fun, sharing my survival tips learned over my 10 years of struggles with an aggressive brand of CLL.

Some of these are broad overarching principles of dealing with a catastrophic illness, and some are very focused suggestions on getting the most out of a doctor's visit or a phone call with our insurance.

They include:

• Put together your team (this is number one)
• Become or find an expert.
• Think laterally.
• You always have time to make a decision, but you don't have forever.
• Risk is impossible to eliminate.
• You have to make decisions with imperfect and contradictory advice.

Lots more but it would be best if you can set aside 24 minutes and perhaps have a pad and paper handy.

The link to my video lecture is here. 

Enjoy.

Please, please, please if you have your own survival and advocacy tips, share them with us at the CLL Society Community using http://cllsociety.org/contact-us/

We welcome your feedback.

As always, all our content is free with no requirement to sign in, but if you want to receive alerts about what's new so you don't miss any important fresh content, please sign up at http://cllsociety.org/newsletter-sign-up/

Thanks

Stay strong

We are all in this together.

Brian Koffman

Volunteer Medical Director of the CLL Society

ASH 2014: Dr. Kipps Explains ROR1 and how CLL (chronic lymphocytic leukemia) is really treated in the Community

When I had a chance at ASH (American Society of Hematology) 2014 to interview my doctor, Dr. Tom Kipps, he first talked about the ROR1 trials that has recently opened at UCSD. This has been his research passion for years and is finally in trials. So far, so good. ROR1 holds the promise to be the perfect cancer target: found on our cancer cells, including possible CLL stem cells, and not on much else.

Keeping in mind that in all likelihood, a curative therapy is going to include a biological or immune approach, so it is important to know about ROR1. I have included links to more background and the clinical trials in the article.

In the second segment of the interview, Dr. Kipps discussed the findings presented at ASH on how CLL is actually treated in the real world. Guess what! It is not according to the latest guidelines. Another reason to add a CLL expert to our team.

These two interviews can be found in the conference coverage (past years) section of the website: http://cllsociety.org

Expect video updates on the website every Monday, Wednesday and Friday for the rest of the month.

ASCO 2014: Dr. Kipps on ABT-199 and more on CLL (chronic lymphocytic leukemia): "Cancer is not an alien from outer space, cancer is us"

More mural work from my son, Ben Koffman

In this final segment of my three part interview from ASCO 2014, my doctor, Dr. Kipps out of the Moore Cancer Center at UCSD, explains as only he can about the competing roles of Bcl-2 and BIM in our malignant B cell clone and how ABT-199 resets that balance in our favor in our malignant B cells.

Here are links to part one and part two of the same interview. They will help set up and give perspective on this longer final segment.

Before you turn off when you hear mention of yet another B cell pathway, please listen to his helpful buttress explanation that explains why this therapy, especially in combinations with other agents, promises a possible cure with no cytotoxic chemotherapy with little collateral damage.

This specific cell death mechanism is particularly active in our malignant B cells. Accordingly, it makes sense as an even more potent target than is blocking B cell communication though the the B-cell receptor (BCR). Blocking BCR activity is likely a major mechanism for the outstanding success of the two newly approved targeted oral agents, idelalisib and ibrutinib. ABT-199 works differently. It works directly on the cell's life and death pathway.

As those who have read my prior post know too well, ABT-199's very potency is its weakness too. It can kill the cancer so fast there is a risk that the kidneys can't keep up with the flood of intracellular toxins spilling out of the millions and millions of lysed (broken down) cancer cells. Tragically, at least two deaths have occurred from this tumor lysis syndrome (TLS), and as a result the whole ABT-199 trial strategy was stopped and than revamped, but it's now back and better.

In other posts, I discussed one tragic death that happened in the trial and argue strongly then that its development be continued and I am so glad that has happened.

But when ABT-199 gets out of trials and into the larger community, I worry that TLS may start to reoccur if the education of the community doctors and their patients is not strong enough.

That, my friends, is one of my major goals here and elsewhere: to inform my fellow patients and providers of the changing landscape in managing CLL so we can make smart decisions and get the care we need.

But ABT-199 has gotten some patients to MRD negative status and even allowed durable disease control long after the med is stopped. That is very exciting and appears to be significantly different from the usual results seen with idelalisib and ibrutinib.

In the past I have argued of reducing the tumor burden with Imbruvica or Zydelig, perhaps with a mAB (monoclonal antibody) such as obinituzumab or rituximab, and then cleaning up any residual disease with ABT-199.

I am happy to say that is now a research direction that is being actively pursued.

It's too early to predict how ABT-199 will fit in the mix, but I predict it will play an important role in the future. The bar already has been set high with the robust responses already seen with the first two approved TKIs. It is not unreasonable to dream that the significant extra kick from ABT-199 or one of the new agents could push us to cure.

So  happy to see more research. We must keep pushing for more evolved therapies that offer cure, not just disease control. (Not that I am complaining about the recent advances that have positively changed my life and that of of so many other CLL patients.)

Later I will comment on the recently announced combination of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo) and the oral BTK inhibitor ibrutinib (Imbruvica) in a phase I/II trial for patients with non-Hodgkin lymphoma (NHL). This is another promising and bold path that has me pretty excited.

But before, we move on, Dr. Kipps has more news for us patients from ASCO 2014.

In the last few minutes of the interview, Dr. Kipps takes a step back and forces us to consider a different perspective on the nature of cancer in general and CLL in particular. He reminds us of cancer's primitive embryonic nature and how ROR1, an embryonic antigen, might be a major player not just in CLL but in other metastatic cancers such as prostrate or ovary too. Thinking about cancer and CLL in this way opens us the possibility for new avenues of research and therapy. The anti-ROR1 mAB is a step in that direction.

When I saw, Dr. Michael Keating from MDACC at the AACR hematology meeting last month in Philadelphia,  he told me he is betting on ROR1 as the path to cure.

When Drs. Kipps and Keating agree, it is worth listening. And considering a ROR1 trial.

Please enjoy my interview with Dr. Kipps.



More soon. (By the way, my ASCO 2014 goatee is long gone.)

This is my crazy season of traveling and teaching, so please forgive my tardiness in posting.

I will be at the LRF conference this Saturday, Oct. 25, 2014 in Manhattan Beach, so please join me and say hello. If you have never attended a LRF conference, they are worthwhile on so many ways. Do come and learn and meet fellow patients.

We are all in this together.

ASCO 2014: Dr. Kipps Discusses ROR1 and Information about a New ROR1 Monoclonal Antibody (cirmtuzumab) Trial in Relapsed and Refractory CLL (chronic lymphocytic leukemia)

Mural Detail by my son Benjamin Koffman

I am just back from a very exciting AACR (American Association for Cancer Research) Hematologic Malignancies Conference that was focused on pre-clinical research pointing the way to better therapies in the future for CLL and all blood cancers.

I will be sharing some of the most promising and clinically relevant research from that meeting in Philadelphia over the next several weeks, but first I wanted to post this timely video from ASCO earlier this year with Dr. Tom Kipps out of UCSD as there is now a chance to see how a new promising therapy using cirmtuzumab, an antibody directed at RORI will work in the real world, converting years and years of research into the first in human clinical trial.

If you haven't seen the lead up to our discussion on this brand new and very specific mAb (monoclonal antibody) targeting ROR1, then please revisit this prior post to catch the first part of our interview done in collaboration with my friend Andrew Schorr and his Patient Power team.

Remember that Dr. Kipps is a cutting edge researcher in the field of immunology and this is an immune  therapy. At the AACR meeting in Philadelphia, when I asked the father of FCR, Dr. Michael Keating out of MDACC how I might cure my own CLL, he quickly said ROR1 therapy (both MDACC and UCSD are working on CAR-T directed at ROR1- See this post with Dr. Wierda from back at ASH 2012). For many blood and cancers in general, the path to a cure means inviting an immune therapy onto the team and ROR1 is a very promising and specific target in CLL.

For more background on ROR1 by Dr. Kipps, see this, also from ASH 2012. It's a ton of long and hard bench science to bring these therapies to the bedside. Dr. Kipps has been excited about this for years and it is finally coming to fruition.

I will let Dr. Kipps tell the update of the story.



I love his push for a cure and I love his pneumonia analogy.

Now the trial for relapsed and refractory CLL patients opened recently, not too much later than the hoped for June start date mentioned at ASCO and this new ROR1 antibody, cirmtuzumab is already being used. A few patients have begun the experimental therapy, and though it is way too early to know much of value, so far so good.

Here's the link at clinical trials.gov and here is a news article on the trial.

What I like about this trial that it is an immune therapy with the promise of very little off target damage. I also like that it is so time limited- you get the 4 infusions over 8 weeks are you are done.

The downside risk. This is a Phase 1 first in human trial. Nuff said!

The dose escalation is also a potential turn off in Phase 1 trials as they are always about safety first. The hope is to find the highest dose that is not toxic called the dose limiting toxicity or DTL.

We know from our experience with the tragedies with too rapid a dose escalation with ABT-199 resulting in fatal tumor lysis syndrome (TLS) that slow and easy is the only way to go. Please see this and this and sadly this if you are not familiar with this tragic and instructive story.

The negative consequence of this emphasis on safety is the risk that those in the first few cohort may get too low or a sub-therapeutic dose.

That's why I like that this trial design. I quote from the trial site: "There is intra-patient dose escalation in the first 3 cohorts, followed by the standard 3+3 design for the next 5 cohorts."

What that means is those in the first three groups get a low dose and if they experience no problems a higher and higher dose. After that the dose is fixed for each three patient cohort.

The whole topic of Phase 1 trial design to minimize risk and maximize benefit is complicated and I am no expert, so I welcome comments from those more savvy. This is a link to a nice review article that will help if you want to dig a bit deeper.

Safety comes first and only then is drug efficacy studied more formally in later trials, but that doesn't mean there can be no measurable benefits from this kind of trial. My ibrutinib trial is sort of a phase 1 trial (1b/2) and I see no reason not to expect that this study with reveal positive results and that cirmtuzumab will eventually become an important new weapon in our arsenal to fight CLL.

For relapsed and refractory patients, admission criteria are pretty standard and there is no mention of prior transplant excluding admission to the trial.

ROR1 has been a long long time in coming.

Is it the future? It looks promising and safe in the lab and animal models, but only the clinical trials will tell us for sure.

As I have said before, the science only advances when one of patients facing a tough therapeutic decision decides that joining a clinical trial makes more sense for a host of potential reasons than standard of care. I did and it turned out to be a good bet.

Approval of Imbruvica Frontline for 17p deleted CLL (Chronic Lymphocytic Leukemia) and Important Trials

It's old news (July 28, 2014), but worthy of some reflection that ibrutinib ( PCI-32765 or Imbruvica) was approved frontline in CLL for those of unfortunate enough to have a deletion of the short (petite or p) arm of chromosome 17.

The p53 gene lives on the 17p arm so when it's deleted, there's missing p53. Without functional p53, cancer cells don't die very easily of apoptosis, the programmed death pathway built into all cells that allows them to suicide when they get too old to function, or in the case of our leukemic cells, become increasingly aberrant and dysfunctional. Without  the tumor suppressing p53 gene, the "guardian of the genome", protecting and repairing our DNA and if that fails, then starting to fire up the self destruction pathway, our cancer continues to grow and mutate and get weirder and more aggressive and difficult to treat.

Most chemotherapy works with the help of p53, first damaging the DNA itself, but then needing the p53 to take it from there by recognizing the overwhelming damage and then persuading the injured cell to die. No p53, and we get just the  chemo induced DNA damage, but the cell can live on and even reproduce faulty clones of itself. That is one reason 17p deletion carries such a bad prognosis.

Until we had ibrutinib (and now also idelalisib or Zydelig), our choices for treating 17p deleted CLL were poor- There were and are a few other therapies that do their killing independent of p53 induced cell suicide. Campath works if you don't have any big nodes, but comes with high infection risks. HDMP (high dose methylprednisolone) + R (rituximab) and flavoperidol and even lenalidomide helped some.

No great choices, until now.

I quote from the press release about the trial that lead to the ibrutinib approval:

At baseline, the median age of these patients was 67 years, 58% of whom had at least one tumor  >  5 cm, and 32% of whom had the del 17p mutation. Patients receiving IMBRUVICA demonstrated a statistically significant improvement in progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) as compared to patients treated with ofatumumab. The median PFS and OS has not been reached on the IMBRUVICA arm. There was a 78% statistically significant reduction in the risk of progression or death as assessed by an independent review committee (IRC) according to the modified IWCLL criteria (HR 0.22, 95% CI, 0.15 to 0.32). In addition, the analysis of overall survival demonstrated a 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA arm (HR 0.43; 95 CI, 0.24 to 0.79). This was observed despite a total of 57 patients who were initially randomized to ofatumumab crossing over to receive IMBRUVICA prior to the analysis. For previously treated del 17p CLL patients, there was a 75% reduction in the risk of progression or death as assessed by an IRC (HR 0.25, 95% CI, 0.14 to 0.45).

Ibrutinib seems to do well on all the folks like me with a missing 17p chromosome on our FISH test, and probably even better for the treatment naive 17p deleted patient. Here is another abstract from the NIH on the subject.

This is good news, right now for just those 17p deletion frontline, but I hope it is only the beginning.

I believe these drugs and others in the pipeline need to be available to all appropriate treatment naive patients, not just those with 17p deletion.

It shouldn't be that most of us have to fail chemo first before being offered less toxic options. The ibrutinib data from the earliest trials suggest those who get ibrutinib upfront before any chemo do the best.

That is why there are some really important clinical trials out there to consider for those who will soon be needing their first treatment for their CLL. Here are a few of my favorites.

With ibrutinib or Imbruvica:

Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

With idelalisib or Zydelig or CAL101: 

A Study of Idelalisib (GS1101, CAL101) + Ofatumumab in Previously Untreated CLL/SLL

A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL

Efficacy and Safety of Idelalisib in Combination With Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia With 17p Deletion (Havasu)

Efficacy and Safety of Idelalisib in Combination With Bendamustine and Rituximab in Subjects With Previously Untreated Chronic Lymphocytic Leukemia

With ABT-199 or GDC-0199:

A Study of GDC-0199 (ABT-199) in Combination With Obinutuzumab in Patients With Chronic Lymphocytic Leukemia

This is by no means a complete list. There are at least 222 trials when you search untreated CLL on Clinicaltrials.gov.

These trials are critical so we can finally prove, as I suspect, that moving these drugs upfront and avoiding chemo all together, is our best course for a long and healthy life.

There are a few other exciting early trials using ROR1 for relapsed disease that Dr. Kipps will be discussing in my next post, an interview from ASCO. ROR1 may prove to be the holy grail of a marker that is truly unique to the CLL cells, making it the perfect target for an anti-cancer drug.

UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia

This is with a very exciting and very specific antibody developed by Dr. Kipps' team at UCSD. It should be opening very soon.

Autologous ROR1R-CAR-T Cells for Chronic Lymphocytic Leukemia (CLL)

This is from Dr. Wierda's team at MDACC and CLL Global Alliance, building on the promising work out of U. Penn with CART-T cells directed at the much less specific CD19.

Both these are phase 1 trials with all the risks and possible breakthroughs that come with being early to a new therapy. My ibrutinib trial, though later in development, was still a phase 1/2 trial.

There are growing choices out there for those of us facing therapy for the first time, and for those who have relapsed. 

Clinical trials are the only way our knowledge can grow, and the only way these drugs will ever become widely available.

And clinical trials are for many of us, especially in frontline settings, the only path to getting these new agents. 

Speaking of new drugs being available, July 28 was also the date that the FDA gave final approval for Ibrutinib for those who have received one prior therapy. The accelerated conditional approval six months ago had been based on phase 2 data, the final approval looked at the big phase 3 RESONATE trial data.

More from Dr. Kipps on ROR1 soon from our interview at ASCO 2014.

Celebrating My Two Year Anniversary Today on Ibrutinib for My CLL (chronic lymphocytic leukemia)

Much has happened in the last two years, most of it very good.

On a personal note, I swallowed my first 3 battleship grey capsules of PCI-32765 (it wasn't even called ibrutinib yet) on May 7, 2012 in a Phase I/II clinical trial at OSU with Dr. Byrd.

Two years later my lymph nodes have shrunk to less than 1/2 their size with the possibility that all that remains on the CT scans is the scarred shells of what used to be cancerous nodes.

Today, to find any CLL in my blood, you can no longer rely on the standard bloods test but must do the vey sensitive flow cytometry to find the < 0.3% of cells that are still clonal.

My latest bone marrow biopsy was 15 months ago in Feb. 2013 and even back then it showed only 4% CLL by flow cytometry down from between 10%-20% a year earlier.

I am clearly in a very deep and deepening remission.

I am very grateful.

On a community note, ibrutinib, the first in class signal blocker (BTK) for CLL, received breakthrough approval in the USA for anyone who has tried at least one prior therapy based on its outstanding safety and efficacy data in all patient groups, including those with 17p deletions and other hard to treat clones. But it is broadly available to any of us who have tried but not necessarily failed just one prior therapy.

Obinutuzumab, a potent 3rd generation monoclonal antibody (mAb) is now on the market and is getting complete remissions with the wimpy help of a touch of chlorambucil in clinical trials. Clearly it is this new mAB that is doing the heavy lifting.

Idelalisib, another  exciting targeted oral medication, should be approved later this year based on its stellar efficacy results in pivotal trials with few adverse events.

ABT-199 is proving to be perhaps the most potent oral agent yet in difficult to that patients.

ONO (ONO 4059) and Infinity (IPI 145) and others have very promising signal blockers well into development.

ROR1 trials are just beginning and should offer laser like focusing and very little off target damage.

CAR-T therapy has pulled a handful of patients from near death to deep remissions.

I was revising a 2012 CME (continuing medical education) on CLL program that I will be giving in Baltimore in June and realized just how far we (and I personally have) have come.

I am very grateful.

After  all, we are all in this together.

I think I''ll enjoy some  home made coconut milk yogurt to celebrate the amazing progress.

ASH 2012: Dr. Bill Wierda on CAR-T Therapies and "Off the Shelf" T-Cells

Dr. Bill Wierda out of MD Anderson Cancer Center (MDACC) is doing important cutting edge immunological research in CLL and looking to improve and make CAR-T therapy a safer and more generic treatment option.

In the first part of my interview from ASH 2012, he explains how he is moving forward in engineering T- cells to target the CLL clone and spare the normal B-cells.

These are early days, but there is surely a vision of an exciting future that is becoming clearer and brighter. Think of these souped-up T-cells doing the work of an allogeneic transplant without all the associated risks. Imagine them seeking and destroying our cancer cells and passing harmlessly by our normal cells.

Dr. Wierda does not minimize the risks or the work left to be done, but the journey has begun. There have been startling successes at U. of Penn and MDACC and UCSD and collaborating on finding better targets to attack and quicker and cheaper ways to engineer these killing machines.

Take a look at my recent post with Dr. Kipps on ROR1 to set the stage.

This work is particularly important because since it was recorded, it has been revealed that some patients with CAR-T directed against CD19 are relapsing because the clone is losing its CD19. Clever nasty cancer.

Poor patients now not only have an aggressive CLL relapsing, they also have no B cells and next to none antibodies, probably forever.

More to come soon.

Exciting and promising and challenging times.

ASH 2012: Dr. Tom Kipps ROR1

In this short final segment from my ASH 2012 interview, Dr. Kipps explains an exciting new target for CLL, ROR1 that seems to almost exclusively exist on cancer cells, making it an extremely attractive target for a vaccine, a monoclonal antibody, or CAR-T therapy.



Please excuse the bursts of static.

Soon I will be ASH 2012 interviews with Drs. Wierda on CAR-T,  Dr. Furman on his experience in the early trials with the TKIs, and an overview with Dr. Wiestner.

Pretty exciting stuff.