| |
Clinical Trialselpt
Meeting With Berlex Labs
June 29, 2024
by Chaya Venkat
FluCam-106
Last week PC and I met with Berlex Labs in
Seattle, at their request. Berlex is the U.S. distributor of Campath,
fludarabine and Leukine (GM-CSF). I am sure they make or distribute other great
stuff, but these days I am not ashamed to admit I have tunnel vision: if the
drug has nothing to offer CLL patients, I am not interested. And for those of
you with "inquiring minds", yes, Berlex did offer us an honorarium for our time.
Both PC and I chose to have their entire check made out to Mayo Clinic,
earmarked for CLL research and Project Alpha. So both of us are still as pure as the
driven snow, no taint of pharmaceutical money to cloud our judgment.
We met with Berlex's marketing and clinical
team. They wanted our input and perspective as patient advocates, and we were
happy to give it to them. We also participated in a CLL patient focus group
discussion. All in all, nice folks, great town, very interesting conversations,
tiresome airports and flights. I have tried to capture much of what we discussed
with Berlex, as well as a little background information where I though it might
be useful to you.
Fludarabine and Campath: Major Drugs
on the CLL Landscape
Let's face it, like it or not chemotherapy is
an important weapon in our arsenal against CLL and fludarabine is as big as they
come in the list of chemotherapy agents for CLL. It has long been the "gold
standard" for CLL, and even now it plays a major role in combination therapies
such as FRC and RF. But please do read our recent article on the use of single
agent fludarabine as front line therapy:
Fludarabine Monotherapy No Longer the Gold Standard. The Ohio State clinical
trial of (Rituxan + fludarabine) combination has demonstrated clear survival
advantage over single agent fludarabine. At this point in time, the other
Berlex CLL-specific drug, Campath, is the only monoclonal antibody that has been
approved for CLL as single agent therapy. Rituxan has
not been approved in this role. And yet, more and more patients are choosing
Rituxan-based therapies, either as single agent or in combinations, and
oncologists are going along with that, sometimes prescribing Rituxan for
off-label use. For many patients, the line-up of escalating therapy intensity
goes something like this right now:
-
Watch & Wait (and Worry);
-
Rituxan as single agent ;
-
Rituxan plus various immune system
modulators, such as Neupogen, high dose corticosteroids, Leukine, IL-2, PT-100
and so on;
-
Rituxan plus fludarabine (and/or
cyclophosphamide, depending on where you go for your expert opinion);
-
All, some or none of the above, plus
Campath for extra oomph or consolidation of minimum residual disease;
-
bone marrow transplant (auto, mini-allo,
full allo).
Obviously, this list is an
oversimplification, and does not fit all cases. There are other drugs such as
Pentostatin (purine analog similar to fludarabine), older generation drugs
like chlorambucil, new stars that are yet to prove their worth such as
flavopiridol, disappointments like Genasense, double helping of monoclonal scenarios like (Rituxan + Campath), the odd "gene therapy" and externally
grown armies of killer T-cells thrown in for good measure. A few
well-constructed clinical trials have addressed frontline and
second-line therapy with Campath, but this is hardly setting the patient
community buzzing with excitement. What gives? No wonder Berlex's Campath team
wanted to meet with us.
Here Is Why
We Think Patients May Be Voting With Their Feet for Rituxan-Based Therapy:
-
Campath targets not only B-cells, but
also T-cells and NK cells. Recent studies have shown that with Campath therapy
the immune suppression is deep and across the board, and some of the cell
lines are mere ghosts of their former selves even 18 months after end of
Campath therapy. Ask us for a reference, if you wish to read the article.
-
Campath has a history of
significantly more infusion-related adverse effects than Rituxan. The fact is,
intravenous Campath administration can be a real bitch, but Campath
administered as a subcutaneous injection has been a lot more tolerable from
the patients' perspective. I wonder why any one would still use intravenous
Campath administration?
-
There is significant risk of
opportunistic infections with Campath, but this is now much better controlled
with mandatory pre-medications to guard against them. However, one question
that has been bugging me: why is there no push to use growth factors such as
Neupogen, to help boost neutrophil counts? Surely these intrepid fighters of
our immune system can help hold the line against infections after Campath
therapy? Good to know neutrophils do not express CD52, so they are not likely
to get killed by the Campath that is still sloshing around your system for at
least a few weeks after the last shot.
-
The recent German clinical trial using Campath
for consolidation of minimum residual disease had to be halted mid-stream, due
to unacceptable level of adverse effects. While a similar trial at M. D.
Anderson was taken to completion, in this reporter's opinion those results
were none too pleasant either. You may want to read
Hitting a
Home Run With Campath Consolidation? to refresh yourself on the details of
this experience.
-
With good reason, patients may be
choosing to keep Campath for a rainy day, when and if they stop responding to
Rituxan-based therapies.
-
There is a wealth of excellent
technical papers describing Rituxan pharmacology and mechanism of action,
providing the comfort factor to local oncologists, patient advocates like me
and patients like you. Much less so with Campath - frankly, we (and the
research community) are still not clear how exactly Campath works. Couple that
with the remarkably low infusion-related side effects of Rituxan, it is easy
to see why Rituxan is the path of least resistance for most of us and our
oncologists.
-
Genentech is an extremely powerful
marketing machine, and it is hard to miss the name Rituxan at any of the major
conferences, oncology journals or even the lay press. I ran into several of
their very persuasive sales reps in oncologists' offices, even got a
ball-point pen. No doubt Rituxan is offered at very attractive "bulk discount"
prices to oncologists. This is a billion-dollar ball game for Genentech.
However, It Is Not In
Patients' Interest to Let This Become a One-horse Race:
Let me get my personal opinion right on the
table, so you can judge what I have to say in the context of my acknowledged
bias. I think Campath is a very important monoclonal in our fight against CLL,
and it is in our interest to support research and clinical development of this
and other such drugs. Here are my reasons:
-
Not all CLL patients respond to Rituxan -
some patients express hardly any CD20 on their CLL cells, the marker that is
targeted by Rituxan.
-
On the other hand, Campath's target,
CD52, is abundantly expressed by just about every
B-cell in your body. Just about all CLL patients respond to Campath, in some
fashion.
-
Campath responses are more robust, deeper,
and seem to last longer than those from Rituxan therapy.
-
The "kinder & gentler" response to Rituxan
therapy may be reflecting nothing more than a shallow response. When Rituxan
based therapy is goosed up with immune modulators such as Neupogen, so that
the response is deeper and more robust, this may be a paralleled by
an increase in the risk of opportunistic infections. Do read
Latest on Harvey, about a patient whose Rituxan-based therapy led to very low absolute lymphocyte
counts, and, sure enough, opportunistic herpes infections.
-
There is a great deal of cross-talk
between B-cells and T-cells and one of the hallmarks of CLL is the very high
risk of autoimmune diseases, some of them precipitated by corruption of the
T-cell compartment by the malignant CLL B-cells. Getting rid of the whole kit
and caboodle may not be such a bad idea, a little bit like firing the
entire corrupt police department as well as the politicians that were on the
take.
-
Campath therapy protocols are improving,
both in efficacy as well as in controlling side-effects. It may be time to
revisit the earlier bad press since it may no longer be relevant. (Read
Campath - Looking Better and Better.)
-
A recent excellent report from our
European CLL experts confirms an important point: Campath works in fludarabine
refractory and poor cytogenetics patients. This has not been shown to be the
case with Rituxan. In fact, CLL patients with prior chemotherapy under their
belt do not show much of a response to Rituxan monotherapy.
-
Last, but not least: even if you are well
set in your therapy choices and you do not think you will ever need
Campath-based therapy, stop and think. Remember that article
Not the Worst Day of Your Life? Familial CLL is a nightmare reality that
none of us who are parents and grandparents can afford to forget. You may not
need Campath. Your kids just might. What you do now to progress this
technology will help other CLL patients down the road, one of whom may be your
own kid or grandkid.
I hate to see a one-horse race. It really
takes at least two players to keep our capitalist system working right. Where would be
the incentive for improvements in Rituxan and related products, if Genentech
had no competition?
"FluCam
106"
Berlex is interested in a clinical trial
that compares head-to-head the Ohio State type (Rituxan + fludarabine)
combination against Campath + fludarabine. This trial is called "FluCam
106" (some of these guys should go back to marketing 101. Personally, I think
the "Round Headed Kid" or
RHK protocol is a lot cuter name. But then, I admit I am
biased).
Here is a link to
the official trial
announcement at the NCI website. Here are some of the details of FluCam 106:
-
The trial is under the able
supervision of Dr. John Gribben of Dana Farber. That is about as credible as
it gets.
-
It is a multi-center trial. Twenty nine
locations are identified in the NCI
official trial announcement, listed alphabetically by state.
-
They are looking to recruit 150
patients, a large enough group to yield statistically meaningful
information. I am glad to see this - it is frustrating to deal with
under-powered and almost anecdotal studies that are called clinical trials
these days. In such trials patients are risked in the name of 'cool' science and
skimpy data of dubious value.
-
Patients will be
randomized
into two arms: one arm will get Rituxan + fludarabine,
the other arm will get Campath + fludarabine. Make sure you understand this
part. Once you volunteer for this trial, you do not get to choose which of the
two arms you will be in, the computer will assign you to either arm, in a
random fashion.
-
Both arms will be supported by
appropriate prophylactic medications to protect against infections.
-
The eligibility criteria require
patients with one (and just one, no more and no less) prior exposure to
therapy.
-
Both arms of the study have heavy
duty blood monitoring, including three (count them, three) bone marrow
biopsies.
-
The trial has been open for 10 months, they
have recruited 12 patients thus far. A little on the slow side, even for these
days.
It is no secret the average
community-based oncologists make much of their annual income based on
difference between the "bulk discount price" they pay for expensive oncology
drugs, and the much larger figure they are permitted to bill insurance
companies or Medicare. This is a huge financial disincentive for referring
patients to clinical trials. That is the single biggest reason why cancer
clinical trials in this country are doing so poorly at recruiting volunteers.
Patients just don't hear about them from their community-based oncologists!
The solution is simple: recruit patients directly, without going through the
local oncologist as middleman. This is where the Internet and patient advocacy
groups like CLL Topics can make a huge difference. We are interested in the
clinical research, we will participate and help the process. But only if we
are taken seriously as legitimate partners in the process, our voices heard,
our input sought. It seems this is a "novel" idea, to have patients considered as
something more than passive cancer victims in the clinical trial
process. Well, time to change that outmoded paradigm, don't you
think?
Recruit
Where the Interest Is, Among Patient Communities
Here is the advice we gave the Berlex
team. They listened very politely and we even think we convinced them on some of
the issues. But if I have learned one thing in my business career, no deal is
a done deal, not until it is really done. As some guy said, at this point the
fat lady is just humming
and a lot can change.
-
Get
away from IV Campath, once and for all. Subcutaneous injection is now the
standard of care for Campath. I am glad to see this is the case in FluCam 106.
-
Systemic corticosteroids to control
infusion-related side effects worry me. One of the comments of the German MRD
study team was that greater use of systemic corticosteroids may have been the
cause of higher than expected adverse effects in their study. Why not use
local corticosteroid cream, at the injection site? This is not my bright
idea, this suggestion comes from an accredited Campath expert, Dr. Geoff
Hale. Geoff, you are a scholar and a gentleman.
-
We strongly urge the use of growth factor
support to control the depth and duration of immune suppression after Campath
based therapies. Not only will this help protect patients against neutropenia
at a time when they are also lymphopenic, there is the intriguing idea that
both Neupogen and Leukine are known to interfere with the SDF-1 and CXCR4
interaction that keeps CLL cells tethered in their cozy lymph node
homes. Kicking them out into the peripheral blood will make them that much
easier to kill. This is one part of the
rationale behind our "RHK" protocol. (read
Adhesion, Homing and Resistance to Therapy and
The Difficult Case of the Round-Headed Kid). It makes even more sense in
the context of monoclonal therapy, since neither Rituxan nor Campath are
particularly good at clearing lymph nodes.
-
Since Campath has a stronger response
compared to its rival Rituxan in the case of patients with poor prognostic
cytogenetics, we suggested that Berlex should be pushing FISH analysis for all
it is worth and in this way play to their strengths. (Read
What
Type of CLL Do You Have?,
FISHing for
Answers,
What You and Your Oncologist Need to Know about CLL (aka Mayo Best Practices).)
Frankly, we suggested that Berlex should start a CLL patient registry, with
free FISH testing for all registered CLL patients. I
am sure they can negotiate a hugely discounted price for the FISH testing from
the several commercial labs that now offer CLL FISH panel, much better price
than we can get one patient at a time. Talk about winning friends in the
patient community. Who needs ball point pens or T-shirts advertising
Campath? Give us FISH instead. You know, I can't bet on this but I think we
might have actually "sold" this idea.
-
We need greater disclosure. Why is it
so hard to get the full blown details of the clinical trial protocol? Every
time I ask for this (and this is not just Berlex's problem but across the
board) I am told the document is proprietary and confidential. I just don't
get it. They are asking patients to sign informed consent forms, risk their
very lives, and the protocol that will be followed by the clinical trial team
is considered not appropriate reading material for patients? How is this
informed consent? Surely this is against the spirit of the Declaration of Helsinki, which laid down very strict ethical regulation of trials
involving human subjects? And here I thought the AMA
was one of the original signatories to that declaration!
-
Forget the deep dark secrets of the
full clinical trial protocol, how can patients make decisions about enrolling
when it is sometimes so hard to get even a full listing of all the locations where
a
trial is offered? Trials like the FluCam 106 protocol last several months and the
monitoring stretches out even more. No one wants to travel far from home for
cancer therapy, if it can be helped. For the patient, this is an important part of the decision
making. Clearly, this information should be widely available. As you
can see from the listing in the
NCI website, FluCam106 has the distinction of being offered in 29 widely
dispersed sites.
-
In the real world of people living on
retirement income or even just social security, cost of clinical trial
enrollment is a real issue. Often, medical insurance pays for "standard and
regular care", and the clinical trial sponsors pay for extra drugs and testing
that is required for the clinical trial. But no one pays for travel costs,
hotel costs, food bills while away from home and other similar out-of-pocket
costs. I think the Berlex team is now convinced that this has to be
changed. But again, check before you sign on the dotted line, make sure you
understand who takes care of the expenses.
-
Believe it not, the abbreviated
clinical trial description of FluCam 106 on the web right now says (in capital
letters for emphasis!) that the trial does not pay for any of the drugs. Huh? That does not compute. Fortunately, I think this one has also been
reconsidered and the trial sponsor will pick up the costs of the Campath and
Fludarabine. Question to ask, what happens if you are randomized into the
Rituxan + fludarabine arm? Who pays for the drugs then? You know me, trust but
verify. Choosing a clinical trial is at least as important as buying a new
car. You do ask for a written price quote from the salesman, right?
-
Three bone marrow biopsies are on the
protocol as of now. I suppose this is not too much to ask, if every one is
guaranteed an expert such as "Larry" at M. D. Anderson, the guy has magic
hands. Most of you will be getting your protocol administered at a local
center. Getting a
bone marrow biopsy done by someone who has not done a zillion of them and
gotten good at it is not a trivial thing. We tried to convince Berlex that
three BMBs are an overkill since a recent article by Kennedy, et. al., has
developed a very nice correlation between peripheral blood data and bone
marrow involvement. Ask us if you want to read the full article. Guys, it does
not have to hurt for it to work well.
-
Last but not least, there is a real
shortage of credible Campath-related information. In the absence of published
literature, I have no option but be shameless and pester the few contacts I
have in the research community with my many questions. Don't you think it
makes sense for Berlex to give an "educational grant" to an unimpeachable
Campath expert, who is then willing and able to answer patients' questions
regarding this important drug? You have no idea how difficult it is to get
busy folks like Dr. Gribben to answer email questions from pushy people like
me, especially to answer the questions "on the record" and OK for publication.
In summary, I think it was a very
fruitful meeting. It says a lot that this company is actually soliciting our
opinion and advice (OK, PC and I might have gone a little over the top on the
advice bit, but hey you get nothing unless you ask for it, right?). I hope
this is a trend and the empowerment that goes with the development of on-line
patient communities will finally get us a seat at the table. We have the
most at
stake in these clinical trials, our lives and our children's lives. Full
disclosure and good faith recruitment that takes the patients' perspective
into account when designing clinical trials just may work, cut through the
so-called patient apathy and distrust.
If Berlex comes through with formal
acceptance of any of these recommendations, we will publish their letter on
our website as well. Patients sign very formal contractual documents when
they volunteer for clinical trials, we ask for no less from the sponsors of
the trials.
You can contribute to support our efforts.
If you think what we do is worthwhile,
please do show your
support.
P Top
|