CAL-101 for untreated symptomatic low-risk CLL

[Guest guest]

Re: Re: CAL-101 for SLL ~ Untreated Patients

At 01:09 PM 3/9/2011, karlamonyc wrote:

>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've been considering communicating, in some form, with Calistoga and

their investigators of CAL-101. Posting on this list is a beginning.

At 01:09 PM 3/9/2011, karlamonyc wrote:

>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.

Actually, it's the 'symptomatic' low-risk untreated CLL patients that

were the focus of my comments. Symptomatic previously untreated CLL

patients have been the subjects of clinical studies of other CLL

drugs in which benefits have been assessed.

In the recently published results (Woyach et al.), in which only

partial disease elimination was achieved in response to FR, it was

the low-risk (IgVH-mutated) untreated symptomatic patients who

benefited from long-term PFS & OS. Similarly, CAL-101 monotherapy

also only achieved partial disease elimination in relapsed/refractory

patients, yet demonstrated efficacy in some of these

patients. Higher-risk (positive for 11q del) untreated symptomatic

patients had poorer PFS & OS in response to FR.

Abstract: http://jco.ascopubs.org/content/early/2011/02/14/JCO.2010.31.1811

Because CAL-101 monotherapy is a very different therapy

(mechanistically, lower-tox) than FR, CAL-101 monotherapy should be

examined in both low-risk and high-risk untreated symptomatic CLL

patients. This is a scenario in which a head-to-head comparison with

an approved therapy (e.g. FCR), although adding a lot of expense, may

be a good idea, for marketing reasons.

Low risk patients are defined by mutation status and absence of

genetic aberrations. However, a slow rate of progression of

untreated patients (to the point of having symptoms needing

treatment) may be another (even better) indicator of " low-risk " for a

treatment (like CAL-101 monotherapy) that only partially eliminates

disease, but sufficiently to eliminate or reduce pathologies to a

manageable level.

At 01:09 PM 3/9/2011, karlamonyc wrote:

>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).

One might expect that rapid accrual of untreated symptomatic patients

(i.e. with pathologies that require treatment) for a trial of a

treatment like CAL-101 monotherapy, with demonstrated very low levels

of toxicity.

At 01:09 PM 3/9/2011, karlamonyc wrote:

>This is an proposal that could only fly if presented to an

>NCI-funded cooperative group.

Calistoga is already running a trial involving untreated symptomatic

CLL patients, except the CAL-101 is combined with Rituxan. It's not

too big of a leap (backwards) to run a trial of CAL-101 monotherapy

in untreated symptomatic patients.

At 01:09 PM 3/9/2011, karlamonyc wrote:

>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.

As I outlined in a previous post (3/8/11) in the original thread

( " CAL-101 for SLL ~ Untreated Patients " ), a business case may be made

for a trial of CAL-101 monotherapy in untreated (low-risk)

symptomatic CLL patients. The basis for that case is related the

combination of CAL-101's demonstrated very low toxicity and the

possibility of long-term PFS & OS efficacy, without achieving MRD

negativity, which lowers risk of therapy-induced secondary leukemias.

The primary business motivation for Calistoga to conduct this trial

sooner, rather than later, may be competition with other companies

developing kinase inhibitors that likely will provide similar values

to CAL-101.

If Calistoga is convinced to conduct a monotherapy trial in untreated

symptomatic patients, that may also set a new clinical development

precedent for earlier testing of that scenario by the sponsors of

those alternative competing kinase inhibitors.

Al Janski

=======

At 01:09 PM 3/9/2011, you wrote:

>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