Re: Shah on Treatment of IM-Resistant CML

[Guest guest]

At 07:20 PM 12/22/05 -0500, you wrote:

> In

>fact it worked as well ­ and maybe even better than ­ the twice a day dosage

>schedule that was later adopted. I really don¹t understand why they began

>with only a single daily dose, and would appreciate any insights any of you

>may have.

Hi ,

The phase 2 trial that I started a month ago, (called Study 34 I think) is

a 4 arm

trial...........50mg BID or 100mg once a day or 70mg BID or 140mg once a day

I am on 100mg once a day.

Happy skiing to you......and I hope you have some time by the fire to keep

sharing all your learned with us.......Thanks.

love, Maui Nanc

[Guest guest]

Hi ,

Thank you again for these amazing reports from the ASH conference. Not

only do you have a great writing skill, you also have the ability to

make the content of a difficult and technical paper easy for a layman to

understand.

I'm sure that you remember Rowbotham's reports from ASH. They were

excellent. I think that your reports are better because you have the

medical background to really make them clear.

Please keep it up. Can't wait to hear what Hochhaus had to say. I know

that early in the game when I spoke to Dr. Druker about a cure for CML,

he thought that it would come in the form of a combination therapy.

Zavie

[ ] Shah on Treatment of IM-Resistant CML

Hi Folks,

Following is the fourth of five presentations from the Friday Corporate

Symposium sponsored by Bristol Myers Squib, which I began reporting on

some

time back. This presentation was by Dr. Neil Shah of UCLA, on Treatment

of

IM-Resistant CML. After this, and one more by s Hochaus, I will

then

have three more multi-speaker talks to go, along with a bunch of really

interesting ³poster sessions.² I apologize taking so long already. The

idea

of reporting on all that remains seems daunting; however, I'm scheduled

to

ski for five days after Christmas, and since the conditions in Maine

then

are notoriously miserable (unless you¹re a teen) at this time of year,

I¹ll

probably spend a lot of time by the fire working on my reports to y¹all.

Shah reviewed the fact that AMN107 (AMN, from now on) is chemically very

similar to IM from which it was derived, whereas Bristo Myers Squibb¹s

BMS354825 (dasatinib, or DS, for the purposes of this lazy typist) is

structurally unrelated to Novartis¹ drugs. Both AMN and DS are at least

2

logs (two powers of ten, or 100x) more potent than IM, so they offer

hope

for effective treatment even in patients whose cells have learned to

over-express the bcr/abl enzyme (brief review: BCR/ABL is the CML cancer

gene [oncogene], whereas bcr/abl [in small letters] refers to the

tyrosine

kinase enzyme that BCR/ABL codes for, and which actually causes all the

bad

things in CML: increased growth and lifespan of the white cells,

increased

mutation rate of these white, so that the disease becomes increasingly

cancerous, etc. For ease of typing, I¹m following the convention of

many

authors nowadays, in referring to the BCR/ABL gene simply as ³BA² -

though

I¹ll continue to refer to the enzyme as bcr/abl).

One reason for the increased potency of these new drugs is that they are

more ³tolerant² of bcr/abl¹s different shapes (called ³conformations² in

the

biochemistry's quaint lingo): they bind to bcr/abl no matter whether it

is

³open² (inactive), ³closed² (active), or in any intermediate stat. IM,

by

contrast, only binds to the closed/active conformation.

In theory, DS offers even greater efficacy because it inhibits not only

bcr/abl, but also one of the kinases (one called src, and pronounced

³sarc²)

responsible for carrying out bcr/abl¹s downstream dirty work (Note: Shah

didn¹t address whether scr inhibition actually makes a difference

clinically

­ nor did I find this out elsewhere at ASH. Do any of you know whether

DS¹s

src-blocking has proven clinical utility?).

Shah mentioned a curious thing about the dosing frequency of dasatinib:

although DS has a half life of only a few hours (5-6 times shorter than

IM),

it was initially given only once a day in Phase I trials. This means

that

patients spent much of each day with very low serum levels, which would

be a

total no-no with IM, where continuous serum levels above a certain

threshold

are deemed absolutely necessary to avoid resistance. Whatever the reason

though, they a single dose for a while, and it seemed to work just fine.

In

fact it worked as well ­ and maybe even better than ­ the twice a day

dosage

schedule that was later adopted. I really don¹t understand why they

began

with only a single daily dose, and would appreciate any insights any of

you

may have. Maybe DS is so potent that it remains at a therapeutic level

even

after several half-life periods have passed. But if this is the case,

why

don¹t they just give patients much less of it, but spread it out during

the

day to keep drug levels stable? Were they concerned about reduced

compliance?

A few other facts:

€ While AMN and DS treat most IM resistant mutations, they engender some

new

resistances of their own. Surprisingly (given that DS and AMN are quite

different molecules), these resistance patterns are rather similar to

one

another. The fact that IM is effective against many of the DS or

AMN-specific mutations and vice versa, is one of the rationales for

trying a

combination of IM and one of these new drugs together. For more on

this,

see the abstract (with Shah as a lead author) at the end of this post.

€ Similar to the IM experience, some patients on DS experienced low

grade

elevations of their liver enzymes (AST, in particular) and of

creatinine.

A new and somewhat more worrisome side effect is pleural effusion (fluid

in

the lining of the lung) experienced by some patients. Jumping ahead of

myself though, I heard at one of the poster session that these effusions

resolve and don¹t tend to recur if you stop the drug for a couple of

days,

give corticosteroids (like prednisone), and then restart.

€ Many IM resistant blast phase patients showed a response by DS, though

as

expected, they shortly became resistant to this drug too (same with

AMN).

€ The ³next frontier² is drugs that will treat T315I, which Shah called

the

³Achilles heel of small molecule TK inhibitors.² None of the drugs that

have reached clinical trials show activity against this mutation, though

several compounds under investigation in vitro show promise (see my

prior

post on IM resistance). Appropriately, some of these compounds have

mysterious, rather heroic names such as the ³Auror kinase inhibitor,² or

(for sci-fi techies), VX680.

OK, off we go with this one. Stay tuned for s Hochaus on the

Potential for Combining Targeted Agents Against CML.

Cheers,

R

______

[1093] Molecular Analysis of Dasatinib Resistance Mechanisms in CML

Patients

Identifies Novel BCR-ABL Mutations Predicted To Retain Sensitivity to

Imatinib: Rationale for Combination Tyrosine Kinase Inhibitor Therapy.

Session Type: Poster Session 251-I

Neil P. Shah, M. Nicoll, Branford, P. ,

L.

Paquette, Moshe Talpaz, Claude Nicaise, Fei Huang, L. Sawyers .

Medicine/Hematology-Oncology, The Geffen School of Medicine at

UCLA,

Los Angeles, CA, USA; Hematology, Institute for Medical and Veterinary

Sciences, Adelaide, New South Wales, Australia; Bioimmunotherapy, MD

Cancer Center, Houston, TX, USA; Bristol-Myers Squibb Oncology,

Princeton, NJ, USA

Point mutations within the BCR-ABL kinase domain represent the most

common

mechanism of resistance to imatinib in patients with CML. Preclinical

studies have shown that dasatinib (BMS-354825) is effective at

inhibiting

the kinase activity of imatinib-resistant BCR-ABL mutants with the

notable

exception of the T315I mutation, which remains highly resistant to

imatinib,

dasatinib, and AMN107 (Gorre et al, Science 2001; Shah et al, Science

2004;

Weisberg et al, Cancer Cell, 2005). Clinical data from Phase I and II

studies of dasatinib in CML confirms the in vitro findings. Each of

three

imatinib-resistant patients bearing the T315I mutation (CP=1; AP=2) did

not

achieve objective hematologic or cytogenetic responses during treatment

with

dasatanib on a Phase I study. Additionally, each of two phase II

patients

with the T315I mutation (CP=1; LBC=1) treated at UCLA showed no evidence

of

objective response. We have also detected the T315I mutation in each of

two

cases of acquired resistance in a phase II (LBC =2) study, and in seven

of

nine patients with acquired resistance to dasatinib in phase I and II

studies (CP=1; MBC=3; LBC=2; Ph+ ALL=1).

Notably, we detected a novel BCR-ABL mutation, T315A, in one of the two

patients who relapsed without a detectable T315I mutation. The patient

is a

53 year-old female whose chronic phase CML had progressed to myeloid

blast

phase while being treated with imatinib. The imatinib-resistant mutation

M244V was identified prior to dasatinib treatment. The patient achieved

a

major hematologic response (<5% blasts with partial recovery of

peripheral

blood counts) on dasatinib 90 mg orally given twice daily, but relapsed

with

MBC after six months. Sequence analysis of the BCR-ABL kinase domain at

the

time of relapse revealed the presence of the imatinib-resistant mutation

M244V as well as the novel mutation T315A. This finding is of particular

interest because T315A and several other novel BCR-ABL mutations were

recently recovered in a saturation mutagenesis study designed to define

potential mechanisms of dasatinib resistance. Remarkably, many of these

mutations retain sensitivity to imatinib in vitro (Burgess et al, PNAS,

2005). Through periodic molecular monitoring of other dasatinib-treated

patients, we have identified a second novel BCR-ABL mutant, F317I, that

developed in an imatinib-resistant CP patient after 9 months of

treatment.

Similar to T315A, F317I was isolated in the saturation mutagenesis

screen

for dasatinib resistance and is predicted to retain sensitivity to

imatinib.

Taken together, our findings implicate the T315I mutation as the

principle

mechanism of resistance to dasatinib, but more importantly, strongly

support

the use for combination kinase inhibitor therapy in CML to prevent

emergence

of drug resistant clones. A phase I trial to assess the safety of

combining

imatinib with dasatinib is planned.

[Guest guest]

Hi ,

I learned about current dosing at the same lecture, but didn't get around to

writing down the schedule in my report. How come you're on a once-a-day

schedule?

Happy holidays, and say hi to my inlaws out there, if you see them.

Love,

> Date: Fri, 23 Dec 2005 00:24:39 -0800

> From: Cogan <ncogan@...>

> Subject: Re: Shah on Treatment of IM-Resistant CML

>

> At 07:20 PM 12/22/05 -0500, you wrote:

>> In

>> fact it worked as well ­ and maybe even better than ­ the twice a day dosage

>> schedule that was later adopted. I really don¹t understand why they began

>> with only a single daily dose, and would appreciate any insights any of you

>> may have.

>

>

> Hi ,

> The phase 2 trial that I started a month ago, (called Study 34 I think) is a 4

> arm trial...........50mg BID or 100mg once a day or 70mg BID or 140mg once a

> day

>

> I am on 100mg once a day.

>

> Happy skiing to you......and I hope you have some time by the fire to keep

> sharing all your learned with us.......Thanks. love, Maui Nanc

[Guest guest]

At 04:44 PM 12/24/05 -0500, you wrote:

>Hi ,

>

>I learned about current dosing at the same lecture, but didn't get around to

>writing down the schedule in my report. How come you're on a once-a-day

>schedule?

>

>Happy holidays, and say hi to my inlaws out there, if you see them.

Hi ,

I guess my note wasn't totally clear......flip of the coin made me once a

day dosing.

The 4 random choices of my Study 34 trial are:

50mg BID

100mg once a day

70mg BID

140mg once a day

So, this trial is looking at the 2 different starting doses and once a day

vs BID.

Dr. Druker's nurse said that the feeling there (with only a small patient

sample) was that

those on once a day dose have fewer side effects than the BID??

After my 3 month BMB, perhaps we will push for something different if we

don't see a good response.

My 'unscientific' thinking was that once a day I am hitting the marrow

really hard (more so than if I was on 50mg BID?????).

You mentioned pleural edema....there are definitely folks dealing with

that. I have a friend who had this right at the beginning but it seems to

have resolved.

I am having some mild peripheral neuropathy (which others on Jerry's BMS

list have written about)....OHSU has cleared me for working with my

naturopath on that. She has me taking 300mg of lipoic acid right now (and

could increase to 600mg)....as this is a treatment for diabetic neuropathy.

About the relatives.....I went to Ian's concert recently. He is really a

good looking kid, and big for 13. says he is going through a

'stage'.......kind of the 'whatever' stage. They keep busy.

Let me know if you have any thoughts about my dose/schedule and the neuropathy.

love, Maui Nanc

>Love,

>

>

>

> > Date: Fri, 23 Dec 2005 00:24:39 -0800

> > From: Cogan <ncogan@...>

> > Subject: Re: Shah on Treatment of IM-Resistant CML

> >

> > At 07:20 PM 12/22/05 -0500, you wrote:

> >> In

> >> fact it worked as well ­ and maybe even better than ­ the twice a day

> dosage

> >> schedule that was later adopted. I really don¹t understand why they began

> >> with only a single daily dose, and would appreciate any insights any

> of you

> >> may have.

> >

> >

> > Hi ,

> > The phase 2 trial that I started a month ago, (called Study 34 I think)

> is a 4

> > arm trial...........50mg BID or 100mg once a day or 70mg BID or 140mg

> once a

> > day

> >

> > I am on 100mg once a day.

> >

> > Happy skiing to you......and I hope you have some time by the fire to keep

> > sharing all your learned with us.......Thanks. love, Maui Nanc

>

>

>

>

>