Re: Off CAL-101 trial, and having problems

[Guest guest]

's experience is most disturbing. has certainly

had more than his share of difficulties with this & his

prior therapies. It would be very important for all of us to

know whether others have had similar experiences when

Cal-101 was discontinued for any reason. 's abnormal

LFTs may resolve off of Cal-101 & he may be able to tolerate

Cal-101 if he resumes it at a lower dose (eg, 50 mg 1 to 2

times daily). If so, it will be important for all of us to

learn what sort of response he then gets.

DR. FURMAN...CAN YOU PLEASE COMMENT ON EXPERIENCE OF OTHERS

WHO HAD TO D/C Cal-101 , especially vis-a-vis rapidity of

regrowth of abnormal LNs?

Good Luck & thank you Dr. Furman for your response,

Rick

[Guest guest]

Hi ,

It's difficult not to be moved and to form opinions from

personal accounts, but it's important to note that both

positive and negative personal accounts from trials truly

must be interpreted with caution. (At least some persons

will experience adverse events from virtually any drug, such

as from aspirin.)

So we can't know from 's account how likely it is that

others will experience the same, ... To estimate that we need

the full reports from adequately powered prospectively

designed studies. As I've said before, the study of drugs

is not done as a formality. We don't know the rate of

benefit and ill until they are adequately studied.

Karl

[Guest guest]

For both CAL-101 and PCI-32765 we have seen the disease

flare when treatment is discontinued. It is hard to know

how to interpret this as the patients who have discontinued

treatment have only been those who really did not respond.

We do not know what that would mean for someone who has

responded, as there is no reason to stop therapy.

What I have done for the two patients I have taken off

therapy for various reasons is covered them steroids or

other therapy. Remember, when PCI-32765 was first started,

we were dosing it for 28 days on and 7 days off. We saw the

nodes grow back and the white count fall during the week

off, which is why the response rate for PCI is higher. When

these patients were evaluated for response, their WBC had

fallen.

Rick Furman

[Guest guest]

Thanks, Rick, for your kind note. I appreciate it.

As far as Karl's response goes, this is a clinical trial.

Karl knows very well that only small numbers of patients are

involved in these trials. Clinical trials are designed to

ferret out problems, to save other potential users adverse

side effects. Should I not share? Should I just keep my

mouth shut?

Every adverse side effect is (hopefully) taken seriously, in

spite of the fact that Karl's dismissive tone implies he

wants to throw out the experience of those with adverse side

effects. " Look at the big picture! "

My point in writing was to convey my experience. I am

having a LOT of problems after coming off this drug, and

they continue unabated.

Certain people who post on this list and elsewhere think

that CAL-101 is 'light-years ahead' of other treatments. If

I knew what was in store for me, I would not have gone on

this trial. Their breathless exuberance helped convince me

to try it. Stupid me. (Or at that British doctor said

about my case, I " just got the sticky end of the lollipop " .

Might as well make light of one man's situation. It's only

one person, you know.)

I'm in a tough position. I don't want to go back on

CAL-101, yet there is nothing else out there that hold even

the hope of shrinking lymph nodes. I wish there was. My

life is pretty much unlivable as it is now.

[Guest guest]

At 07:39 AM 4/28/2011, Rick Furman wrote:

>For both CAL-101 and PCI-32765 we have seen the disease flare when

>treatment is discontinued. It is hard to know how to interpret this

>as the patients who have discontinued treatment have only been those

>who really did not respond. We do not know what that would mean for

>someone who has responded, as there is no reason to stop therapy.

Dr. Furman, thus far, have all your patients, treated with

CAL-101 or PCI-32765, been relapsed/refractory patients?

Relapsed/refractory patients are more likely (than untreated

low-risk patients) to have dominant CLLcell clones that are

more aggressive (rapidly growing). Conversely, previously

untreated and low-risk patients are more likely to have less

aggressive (slower-growing) CLLcell clones dominating

proliferation centers (nodes, spleen, marrow) at the time of

treatment.

Although neither CAL-101 nor PCI-32765 (apparently) is yet

being studied as a monotherapy in untreated patients,

CAL-101 is being combined with other agents (i.e. Rituximab)

in ongoing studies [ http://tinyurl.com/47fvxfc ] of

untreated CLL patients.

It would be interesting to know whether untreated CLL

patients in this combination study who are taken off CAL-101

treatment also have a disease flare comparable to the

disease flare that is being observed when the

relapse/refractory patients who were taken off of CAL-101.

As for why treatment-withdrawal induces a tumor flare in

patients who did not respond clinically, it is possible for

an kinase inhibitor to cause a biochemical response, without

a clinical response. For example, in the CAL-101 study, the

lack of clinical response could be because these patients

may have CLLcell clones with alternative pathways activated

that can by-pass the need for a functional PI3K, but

exposing these patients to the CAL-101 inhibitor could

induce a compensatory increase in PI3K (in the same or

different CLLcell clones), which is inhibited as long as the

inhibitor is administered, but, when the inhibitor treatment

is ended, that additional, induced PI3K is active again to

support the increased CLLcell proliferation that underlies

the disease flare.

Al Janski

[Guest guest]

We have used PCI-32765 in untreated patients over the age of 65.

The cells do die with the enzymes inhibited. I suspect the

flare is related to the resumption of cytokine production by

the stromal cells activating the CLL cells.

When evaluating this " flare " , it is important to remember

that we have not been taking responding patients off of

treatment. The patients discontinuing treatment are most

likely doing it because they are not responding.

[Guest guest]

At 09:41 PM 4/28/2011, rrfurman@... wrote:

>We have used PCI-32765 in untreated patients over the age of 65.

Have these untreated patients, who have not clinically responded to

PCI-32765, had comparable disease flare as relapsed/refractory

patients who have been taken off PCI-32765?

At 09:41 PM 4/28/2011, rrfurman@... wrote:

>The cells do die with the enzymes inhibited.

Is it in vivo or in vitro data that demonstrates that CLL cells die

when BTK or PI3K is inhibited by PCI-32765 or by CAL-101, respectively?

At 09:41 PM 4/28/2011, rrfurman@... wrote:

>I suspect the flare is related to the resumption of cytokine

>production by the stromal cells activating the CLL cells.

Are you then assuming that the inhibition by PCI-32765 or by CAL-101

(in CLLcells or stromal cells?) is providing clinical benefit by

inhibiting the production of cytokines by stromal cells?

At 09:41 PM 4/28/2011, rrfurman@... wrote:

>When evaluating this " flare " , it is important to remember that we

>have not been taking responding patients off of treatment. The

>patients discontinuing treatment are most likely doing it because

>they are not responding.

Yes, however, that absence of response (to CAL-101 or PCI-32765

inhibitors, respectively) could be because these patients may have

CLLcell clones with alternative pathways activated that can by-pass

the need for a functional PI3K or BTK, respectively. And exposing

these patients to these inhibitors could induce a compensatory

increase in PI3K or BTK (in the same or different CLLcell clones),

which is inhibited as long as the inhibitor is administered, but,

when the inhibitor treatment is ended, that additional, induced PI3K

is active again to support the increased CLLcell proliferation that

underlies the disease flare. Inhibitor-induced up-regulation of

enzymes is a common response in many biochemical pathways.

Al Janski

[Guest guest]

Hi , I am of course sorry for the challenges you face

and you have every right to share your account and seek

input.

My point was to ... only that we can't judge a drug

from individual accounts - without a denominator we don't

know if the outcome will occur in 1 in 4, or 1 in 1000.

For example, Rituxan, considered a " safe " drug sometimes

leads to dreadful results in some cases.

All the best,

Karl

[Guest guest]

Re: CAL-101 and cytokine storms

At 01:27 PM 4/29/2011, S wrote:

> I was given to understand that the drug is withdrawn

> when the liver enzymes became elevated. This came

> after being on the drug for three months.

What dose of CAL-101 did you receive?

The protocol indicates " 50 to 350 mg " , and that dosing would

continue " until disease progression or unacceptable

toxicity " , the latter being your situation.

See http://tinyurl.com/3botbm6

At 01:27 PM 4/29/2011, S wrote:

> CAL-101 rapidly decreased the size of my nodes.

Apparently, you were a responder. If I understand Dr.

Furman's patient experience, none of his patient who

responded, so far, have had to go off treatment because of

liver toxicity.

At 01:33 PM 4/28/2011, S wrote:

> I don't want to go back on CAL-101, yet there is nothing else

> out there that hold even the hope of shrinking lymph nodes.

The interim data (reported by Dr. Furman at the ASCO 2010

meeting) indicated increasing liver toxicity (i.e. release

into blood of enzymes " ALT/AST " from liver) with increasing

dose of CAL-101. I do not know whether there is a more

recent report as to whether this relationship is confirmed

with more data.

If you received one of the higher doses (e.g. 350mg), maybe

there might be a lower dose at which the hepatic toxicity is

acceptable while still achieving a useful therapeutic

response. If it took 3 months of treatment before the liver

toxicity was evident, the lower dose may have some chance

for low-tox efficacy, at least for a while.

Al Janski

[Guest guest]

I thought I would share my experiences in response to the

question posed here. My MIL is in the CAL-101/Rituxan

clinical trial for older, previously untreated patients. Due

to a severe bout with pneumonia, Dr. Flinn took her off

CAL-101 for three weeks. She had been taking 150 mg. twice a

day. She had no flare of her CLL during this time. She had

been responding well prior to the pneumonia. And once she

was recovered from that, he resumed her treatment with a

dose of 100 mg. twice a day. She is 78 and doing well.