Re: CAL-101 for SLL ~ Untreated Patients

[Guest guest]

At 05:01 PM 3/3/2011, cllcanada wrote:

>More:

><http://clinicaltrials.gov/ct2/show/NCT01306643?term=CLL & recr=Open & rcv_d=14>htt\

p://clinicaltrials.gov/ct2/show/NCT01306643?term=CLL & recr=Open & rcv_d=14

>Inclusion Criteria:

>Previously untreated low-grade (indolent) B-cell NHL.

>Patient is otherwise medically appropriate for " watchful waiting " ,

>i.e., does not have significant symptoms or indication of incipient

>or immediately impending organ impairment.

Indolent, watchful waiting CLL patients (because of absence of

treatment criteria) would normally not be treated. Presumably, that

is also the case for SLL patients.

As such, it's a bit surprising Calistoga is conducting this study of

CAL-101 monotherapy on untreated SLL patients without symptoms before

it conducts a study CAL-101 on untreated SLL patients who meet one or

more of the standard criteria for treatment. This might be more

understandable if the study was classified as only a safety study,

but it is classified as a safety/efficacy study.

Al Janski

[Guest guest]

I may be all wrong here, but why would someone who is watch and wait

and does not show a need for treatment want to sign up for a clinical

trial involving treatment, no matter how benign????

I will certainly consider what trials are available if I need

treatment, but I see no reason to tempt fate by messing with my system

if it is holding it's own.

Pat

On 3/3/11, Al Janski <aljanski@...> wrote:

> At 05:01 PM 3/3/2011, cllcanada wrote:

>>More:

>><http://clinicaltrials.gov/ct2/show/NCT01306643?term=CLL & recr=Open & rcv_d=14>ht\

tp://clinicaltrials.gov/ct2/show/NCT01306643?term=CLL & recr=Open & rcv_d=14

>>Inclusion Criteria:

>>Previously untreated low-grade (indolent) B-cell NHL.

>>Patient is otherwise medically appropriate for " watchful waiting " ,

>>i.e., does not have significant symptoms or indication of incipient

>>or immediately impending organ impairment.

>

> Indolent, watchful waiting CLL patients (because of absence of

> treatment criteria) would normally not be treated. Presumably, that

> is also the case for SLL patients.

>

> As such, it's a bit surprising Calistoga is conducting this study of

> CAL-101 monotherapy on untreated SLL patients without symptoms before

> it conducts a study CAL-101 on untreated SLL patients who meet one or

> more of the standard criteria for treatment. This might be more

> understandable if the study was classified as only a safety study,

> but it is classified as a safety/efficacy study.

>

> Al Janski

[Guest guest]

Struck me as odd also. I suspect they want to see if CAL101

will in fact slow the progression of SLL.

In other words, for SLL patients, perhaps CAL101 is superior to watch & wait.

~chris

[Guest guest]

I think for those on the edge of treatment and watching the early success of

CAL-101 (and PCI-32765), especially for node reduction, it could be very

tempting. We don't know when these drugs will be available other than in a

trial and we don't know how many more trials the parent companies can afford to

bank roll. I visited Dr. Coutre's clinic at Stanford for consideration for two

untreated patient trials with these drugs and had mixed feelings when I was told

I was not ready for treatment .. first (and foremost) glad that I didn't need

treatment at that moment, but also some fear that when I did, I might have

missed the availability of the drugs and would have to go through the more

treacherous chemo route.

Lynn

>

> I may be all wrong here, but why would someone who is watch and wait

> and does not show a need for treatment want to sign up for a clinical

> trial involving treatment, no matter how benign????

>

[Guest guest]

http://clinicaltrials.gov/ct2/show/NCT01306643?term=CLL & recr=Open & rcv_d=14

At 10:39 AM 3/4/2011, cllcanada wrote:

>In other words, for SLL patients, perhaps CAL101 is superior to watch & wait.

Somehow, it seems that will be a difficult notion to sell to both CLL

specialists and to patients who " do not have significant symptoms " ,

despite CAL-101's minimal toxicities, at least until there is a lot

more history of CAL-101 treatments in numbers of patients and in time

after treatments.

I think we're missing something that is motivating this study of SLL patients.

At 10:54 AM 3/4/2011, lynnb65 wrote:

>I think for those on the edge of treatment and watching the early

>success of CAL-101 (and PCI-32765), especially for node reduction,

>it could be very tempting.

The inclusion criteria of absence of symptoms imply 'SLL' patients on

the edge of treatment because of problems with nodes may not be

considered eligible for this trial.

At 10:54 AM 3/4/2011, lynnb65 wrote:

>I visited Dr. Coutre's clinic at Stanford for consideration for TWO

>untreated patient trials with these drugs and had mixed feelings

>when I was told I was not ready for treatment....

Lynn do you have CLL or SLL? Since you were deemed not ready, I'm

guessing you do not have SLL, given there is this Stanford trial for

SLL patients without significant symptoms.

As such, I assume both of these two (other?) trials of CAL-101 (at

Stanford), for which you were considered, include CLL patients?

Since Stanford is a study site for the CAL-101+Rituximab trial (for

untreated 'symptomatic' CLL/SLL patients), I suspect one of the two

trials may be that trial.

i.e. " A Study of CAL-101 and Rituximab in Elderly Patients With

Untreated CLL or SLL "

http://tinyurl.com/47fvxfc

If both trials at Stanford include CLL patients, then it suggests

that a second CAL-101 trial (monotherapy?) of untreated patients

(with symptomatic CLL?) may be on the horizon, just not yet

publishing its availability.

An important (maybe the best) clinical use of CAL-101 monotherapy may

be for " low-risk " untreated CLL patients who have symptoms requiring

treatment. Hopefully, Calistoga will be conducting such a study soon.

Al Janski

[Guest guest]

Yes Al, I have CLL and not SLL. I'm not sure that there will be a CAL-101

monotherapy for untreated patients offered .. It looks like they have moved into

the world of combining CAL-101 with other agents. The relapsed and refractory so

far are the only ones, as far as I know, who are getting the monotherapy.

And, the only untreated CLL patients offered PCI-32765 or CAL-101+R are

" elderly " . (That is, as far as I know.)

The person who might help us understand the evolution of these trials and what

might be coming would be Dr. Furman. I'm sure he could comment on the trial for

untreated SLL patients.

And Al, I agree with you that an interesting trial would be monotherapy for low

risk patients.

I find your theory re over treatment / wiping out the wrong clonal colony / very

interesting. And if I understand it correctly, keeping minimal disease under

control may be better than wiping the slate clean except for a few nasties, who

can then become the dominant population. (Am I getting it right?) However, not

sure where patients such as I fit in, with 13q deletion but 80-90% marrow

infiltration. Are we still low risk or does the marrow reality trump the

deletions?

Lynn

> Lynn do you have CLL or SLL? Since you were deemed not ready, I'm

> guessing you do not have SLL, given there is this Stanford trial for

> SLL patients without significant symptoms.

>

> As such, I assume both of these two (other?) trials of CAL-101 (at

> Stanford), for which you were considered, include CLL patients?

>

> Since Stanford is a study site for the CAL-101+Rituximab trial (for

> untreated 'symptomatic' CLL/SLL patients), I suspect one of the two

> trials may be that trial.

> i.e. " A Study of CAL-101 and Rituximab in Elderly Patients With

> Untreated CLL or SLL "

> http://tinyurl.com/47fvxfc

>

> If both trials at Stanford include CLL patients, then it suggests

> that a second CAL-101 trial (monotherapy?) of untreated patients

> (with symptomatic CLL?) may be on the horizon, just not yet

> publishing its availability.

>

> An important (maybe the best) clinical use of CAL-101 monotherapy may

> be for " low-risk " untreated CLL patients who have symptoms requiring

> treatment. Hopefully, Calistoga will be conducting such a study soon.

>

> Al Janski

>

>

[Guest guest]

I am an untreated indolent SCLL patient on W & W for over 10 yrs and I'm not

the least bit tempted to join a clinical trial or treatment until my oncologist

says I have to.

No matter how benign it might say on paper, every treatment has a

permanent effect.

[Guest guest]

Who says your oncologist is the final arbiter for your

undertaking treatment? What about second opinions?

I am an untreated indolent SCLL patient on W & W for over

10 yrs and I'm not the least bit tempted to join a clinical

trial or treatment until my oncologist says I have to.

No matter how benign it might say on paper, every treatment

has a permanent effect.

[Guest guest]

There are several issues raised here worth exploring.

Right now, we do not have any data suggesting early treatment leads to better

outcomes, but that does not mean it is not worth exploring. One issue with

early intervention is that the chemotherapy might depleted stem cells and lead

to bone marrow failure. If you have a treatment that does not do that (CAL-101

or PCI-3265), then there is much less downside to early treatment. If would

" tip the balance " toward a benefit for early treatment.

This study is possibly a early stage study just assessing safety of early

treatment with CAL-101. The next step would be to do a randomized study between

early versus standard timing.

It is important to remember that CLL and SLL patients are the same. Some

doctors treat SLL more like a lymphoma and intervene prematurely. If a patient

with another lymphoma has significant LAD, but no symptoms, many physicians

treat.

Regarding the PCI-32765 try in elderly untreated patients requiring treatment,

this population was selected because it is a possible path to approval. It

might be considered unethical to enroll young patients in such a trial because

we have a great deal of data with FCR and that young patients can tolerate it.

Because tolerability of FCR is less in patients over 65, that is how it is

justified. I do not agree with that philosophy and would prefer to see everyone

treated with non-chemotherapy treatments. But this is why medicine is an " art

and not a science " .

Rick Furman, MD

>

> Yes Al, I have CLL and not SLL. I'm not sure that there will be a CAL-101

monotherapy for untreated patients offered .. It looks like they have moved into

the world of combining CAL-101 with other agents. The relapsed and refractory so

far are the only ones, as far as I know, who are getting the monotherapy.

>

> And, the only untreated CLL patients offered PCI-32765 or CAL-101+R are

" elderly " . (That is, as far as I know.)

>

> The person who might help us understand the evolution of these trials and what

might be coming would be Dr. Furman. I'm sure he could comment on the trial for

untreated SLL patients.

>

> And Al, I agree with you that an interesting trial would be monotherapy for

low risk patients.

>

> I find your theory re over treatment / wiping out the wrong clonal colony /

very interesting. And if I understand it correctly, keeping minimal disease

under control may be better than wiping the slate clean except for a few

nasties, who can then become the dominant population. (Am I getting it right?)

However, not sure where patients such as I fit in, with 13q deletion but 80-90%

marrow infiltration. Are we still low risk or does the marrow reality trump the

deletions?

>

> Lynn

>

> > Lynn do you have CLL or SLL? Since you were deemed not ready, I'm

> > guessing you do not have SLL, given there is this Stanford trial for

> > SLL patients without significant symptoms.

> >

> > As such, I assume both of these two (other?) trials of CAL-101 (at

> > Stanford), for which you were considered, include CLL patients?

> >

> > Since Stanford is a study site for the CAL-101+Rituximab trial (for

> > untreated 'symptomatic' CLL/SLL patients), I suspect one of the two

> > trials may be that trial.

> > i.e. " A Study of CAL-101 and Rituximab in Elderly Patients With

> > Untreated CLL or SLL "

> > http://tinyurl.com/47fvxfc

> >

> > If both trials at Stanford include CLL patients, then it suggests

> > that a second CAL-101 trial (monotherapy?) of untreated patients

> > (with symptomatic CLL?) may be on the horizon, just not yet

> > publishing its availability.

> >

> > An important (maybe the best) clinical use of CAL-101 monotherapy may

> > be for " low-risk " untreated CLL patients who have symptoms requiring

> > treatment. Hopefully, Calistoga will be conducting such a study soon.

> >

> > Al Janski

> >

> >

[Guest guest]

At 10:33 AM 3/6/2011, Rick Furman, MD wrote:

>This study is possibly a early stage study just assessing safety of

>early treatment with CAL-101. The next step would be to do a

>randomized study between early versus standard timing.

Dr. Furman, are you aware of any ongoing or pending studies of

CAL-101 monotherapy in untreated symptomatic CLL patients?

If not, is it likely this study, which includes SLL patients, would

be the predecessor to such a study?

Al Janski

At 10:33 AM 3/6/2011, Rick Furman, MD wrote:

>There are several issues raised here worth exploring.

>

>Right now, we do not have any data suggesting early treatment leads

>to better outcomes, but that does not mean it is not worth

>exploring. One issue with early intervention is that the

>chemotherapy might depleted stem cells and lead to bone marrow

>failure. If you have a treatment that does not do that (CAL-101 or

>PCI-3265), then there is much less downside to early treatment. If

>would " tip the balance " toward a benefit for early treatment.

>

>This study is possibly a early stage study just assessing safety of

>early treatment with CAL-101. The next step would be to do a

>randomized study between early versus standard timing.

>

>It is important to remember that CLL and SLL patients are the same.

>Some doctors treat SLL more like a lymphoma and intervene

>prematurely. If a patient with another lymphoma has significant LAD,

>but no symptoms, many physicians treat.

>

>Regarding the PCI-32765 try in elderly untreated patients requiring

>treatment, this population was selected because it is a possible

>path to approval. It might be considered unethical to enroll young

>patients in such a trial because we have a great deal of data with

>FCR and that young patients can tolerate it. Because tolerability of

>FCR is less in patients over 65, that is how it is justified. I do

>not agree with that philosophy and would prefer to see everyone

>treated with non-chemotherapy treatments. But this is why medicine

>is an " art and not a science " .

>

>Rick Furman, MD

[Guest guest]

Right now, most of the studies are focused on combination therapy as CAL-101 is

so well tolerated and combination therapies are the rule, rathter than the

exception.

> >There are several issues raised here worth exploring.

> >

> >Right now, we do not have any data suggesting early treatment leads

> >to better outcomes, but that does not mean it is not worth

> >exploring. One issue with early intervention is that the

> >chemotherapy might depleted stem cells and lead to bone marrow

> >failure. If you have a treatment that does not do that (CAL-101 or

> >PCI-3265), then there is much less downside to early treatment. If

> >would " tip the balance " toward a benefit for early treatment.

> >

> >This study is possibly a early stage study just assessing safety of

> >early treatment with CAL-101. The next step would be to do a

> >randomized study between early versus standard timing.

> >

> >It is important to remember that CLL and SLL patients are the same.

> >Some doctors treat SLL more like a lymphoma and intervene

> >prematurely. If a patient with another lymphoma has significant LAD,

> >but no symptoms, many physicians treat.

> >

> >Regarding the PCI-32765 try in elderly untreated patients requiring

> >treatment, this population was selected because it is a possible

> >path to approval. It might be considered unethical to enroll young

> >patients in such a trial because we have a great deal of data with

> >FCR and that young patients can tolerate it. Because tolerability of

> >FCR is less in patients over 65, that is how it is justified. I do

> >not agree with that philosophy and would prefer to see everyone

> >treated with non-chemotherapy treatments. But this is why medicine

> >is an " art and not a science " .

> >

> >Rick Furman, MD

>

>

>

>

>

[Guest guest]

At 07:16 AM 3/7/2011, Rick Furman, MD wrote:

>Right now, most of the studies are focused on combination therapy as

>CAL-101 is so well tolerated and combination therapies are the rule,

>rathter than the exception.

It is understandable that Calistoga would follow precedents set for

clinical development of previously approved CLL drugs; i.e. starting

with monotherapy studies in high-risk (relapsed/resistant) patients,

then conducting studies (e.g. of untreated symptomatic patients)

involving combinations with some of those approved drugs (with

different mechanisms of action).

It may even make good short-term business sense to explain to current

investors a clinical development strategy that is patterned after

those precedents of successful regulatory approval. Additionally,

it's probably a pretty good bet that the addition of some drugs (e.g.

Rituxan) will add to efficacy of CAL-101 in untreated symptomatic

patients, and the negative effects of that additional drug may not be

a significant detracting factor during the time-frame needed for

initial regulatory approval.

However, those clinical development precedents were built upon CLL

drugs with different biochemical characteristics (e.g. higher

toxicities) than those of CAL-101.

Every product development process in which I've been involved has

included analyses of how our product might be unique and how to

leverage the unique characteristics for better competitive

positions. Calistoga surely did those analyses, and may have decided

none of the opportunities that leverage the unique properties (e.g.

low tox, mechanism of action) were worth veering from precedents.

The partial efficacy of CAL-101 monotherapy in relapsed/refractory

CLL patients was encouraging, given these patients can be expected to

be more likely dominated by aggressive (treatment-resistant) CLLcell

clones than untreated symptomatic CLL patients. As such, even better

efficacy could be expected for CAL-101 monotherapy in untreated

symptomatic patients. The recently published results (Woyach et al.)

of only partial disease elimination by FR in untreated symptomatic

patients, being able to provide long-term PFS & OS, add support to an

expectation of better long-term benefits from an agent like CAL-101

monotherapy that provides only partial disease elimination.

Consequently, making CAL-101 monotherapy in untreated symptomatic CLL

patients a low priority, may be a lost (or at least delayed) business

opportunity for Calistoga. Other similar competing agents (e.g.

PCI-32765) are close behind in the pipeline.

Al Janski

[Guest guest]

Hi Al,

I agree with you regarding the need to evaluate low-toxic targeted therapies in

the untreated asymptomatic population and suggest that you write it up and

submit to the sponsor and CLL investigators.

I made a similar informal proposal at a meeting of investigators (Why not test

in the population that doesn't need treatment in order to improve

enrollment...?) and was shot down with a few words from the chair : ) ... that

it's too difficult to assess a benefit in the asymptomatic indolent population.

.... No detail was provided, but I suppose it has to do with the long and

variable clinical course of indolent CLL/lymphoma and uncertainties about the

meaning of standard surrogate endpoints (PFS, TTP, ORR) early in the disease --

if any of these reasonably predicts a survival benefit, and what the impact of

such therapy might have on response to subsequent therapy.

(The rationale for follow-up (even if after-market follow-up) to include

outcomes from next therapy being that even a targeted therapy could lead to

resistance to standard therapy by unknown mechanisms).

You might note that fast accrual might offset these challenges; and that the

study question is of interest and potentially of vital importance to patients -

who are, btw, the primary stakeholders in research (but not routinely consulted

in such decisions).

This is an proposal that could only fly if presented to an NCI-funded

cooperative group. The sponsor, being a business, will take what they judge to

be the fastest, cheapest and most reliable path to marketing approval -

typically by showing an improvement in PFS in the refractory population.

All the best,

Karl