CML Patient Meeting - Montreal - Part II

[Guest guest]

Hello All,

As promised here is part II

Before getting into part II I did want to mention another milestone that was

celebrated at our meeting.

We all signed a card and celebrated Suzan McNamara's birthday. A

significant date for us all - since it was also the date 6 years ago that

Suzan received the word from Novartis regarding the petition.

Dr. Laneuville spoke to us about a CML registry that has been approved for

Canada. This will be quite helpful to all of us as information on every

patient will be entered into the database - blinded of course. All sorts of

information will be tracked, for instance a Hem/Onc could query the data for

all patients with low Hgb to determine if it is of any prognostic value. As

you can imagine lots of information could be tracked and queried. Hopefully

we'll hear more about this in the future.

Now for Dr. Ravandi's part of the talk.

Most of my notes are from the oncology conference he spoke at here in

Montreal the day before meeting with us, but then again, he presented much

of the same thing. If anyone who attended wants to add anything here,

please feel free to do so.

Dr. Ravandi also covered the history and origin of CML, and presented more

data from the IRIS trial and the from information at MDACC.

Dr. R. spoke about BCR ABL:

It is a tyrosine kinase oncoprotein

Auto and substrate phosphorylation

Highly plastic structure

" open " active versus " closed " autoinhibited state ( IM binds only to the

active form)

State regulated intra-and extra-molecularly

In speaking about Gleevec - Dr. R. said:

other kinases inhibited by IM are:

ABL

Bcr-Abl

PDGFRâ

c-Kit

IM in the Phase I trial

With 25-85 mg/day - only 1 patient out of 10 achieved a CHR (complete

hematological remission - meaning blood counts were alright)

140-250 mg/day- 10 patients out of 19 (53%) achieved CHR and 2 patients out

of 19 (11%) achieved CCR

300-1000 mg/day - 53 patients out of 54 (98%) achieved CHR and 29 (54%)

patients out of 54 achieved cytogenetic response

17 (31%) patients of the 54 achieved Major cytogenetic response

No MTD (maximum total dose/day) was reached.

He also covered the results of the IRIS trial, which was covered already by

Dr. L.

Dr. R. presented data on survival with IM in newly dxed CML comparing

results with IRIS to MDACC

IRIS had 553 patients and 51 months out - ~ 95% were still alive

MDACC had 247 patients and ~ 98% were still alive.

He showed data that was presented at ASH last year showing BCR-ABL levels

continue to decrease with IM therapy in CP CML (28 pts on IRIS study Rx with

IM 400 mg/d

12 mos median log reduction was 3.0 and 46% had a 3 log or better and 4% had

a 4 log or better reduction

24 mos median log reduction was 3.4 and 68% had a 3 log or better and 7% had

a 4 log or better reduction

36 mos median log reduction was 3.9 and 71% had a 3 log or better and 32%

had a 4 log or better reduction

42 mos median log reductions was 4.2 and 71% had a 3 log or better and 54%

had a 4 log or better reduction

Looking at IM 400mg versus 800 mg (presented at ASH 2004 also)

Of 175 patients chosen for the higher dose, 156 achieved Complete

cytogenetic response

of the 50 patients chosen for the lower dose 39 achieved CCR

It is important to note that this was not a randomized trial. That is why

the Gleem trial is happening in Canada, as a randomized trial is needed to

prove the higher dose strategy/theory.

The RIGHT study looked at various doses of IM - 300mg, 400mg, 600mg and

800mg

It had the following endpoints:

Primary: Percent of patients achieving molecular response

Secondary: time to hematologic response, cytogenetic response, and complete

molecular response

- percent of patients with undetectable BCR-ABL transcripts at 12 mos

- Safety

Interestingly this study also showed the level of non compliance (as it

were) in that it showed actual dose of IM over time. In the first 3 mos all

patients were completely compliant at 3 mos - 36 patients were still at

800mg, 8 were at 600mg and 3 were at 400mg, by 9 mos, 15 were at 800mg, 5

were at 600mg and 5 were at 400mg, by 12 mos, 7 were at 800mg, 1 was at

600mg and 3 was at 400mg.

The results of the trial showed that 7 of the 11 patients who stayed at the

800mg dose achieved either a 3 log reduction or better and all 7 also

achieved undetectable. So I guess there is something to be said about

compliance!

He spoke about mechanisms of " resistance " to IM (Bcr-Abl mediated or not)

- Patient not taking drug

- ABL point mutations going to conformation change of ATP binding site or

modulators

- Increase in BCR-ABL, showing BCR-ABL kinase activity

- Metabolic, PK, drug interactions MDR clonal evolution

- ? other kinases - VEGF, mTOR, src

- CML no longer the main problem

Speaking about AMN107:

Showing the molecular structure he stated that AMN107 has a better

interaction between ABL binding - improves the affinity of BCR-ABL to bind

with AMN107.

The conclusions from the Phase I trial of AMN107 are:

Hematologic response rates >50% in AP and BP

Cytogenetic responses in AP and BP

No DLT (dose limiting toxicity) found

Well tolerated up to 1,200 mg daily

Rare liver, skin, or marrow AE's (adverse events)

He spoke about Dasatinib - reviewing Talpaz's work presented at ASH last

year:

Of the 10 patients in BP, 50% achieved CHR, 80% achieved MHR

Of the 32 patients in AP/ALL 28% achieved CHR, 69% achieved MHR

In the same group of CML AP/BP the CG response was as follows:

AP - 40% achieved CyR, 30% achieved CCyR, and 10% achieved PCyR

BP - 56% achieved CyR, 10% achieved CCyR, and 16% achieved PCyR

Of the most commonly reported non hematologic responses:

Elevated ALT (28%)

Elevated Creatinine (23%)

Diarrhea (18%)

Paresthesia (10%)

Headache (10%)

Nausea (5%)

Peripheral edema (5%)

Pleural Effusion (3%)

GI Hemorrhage (0)

These were of low grad 1 - 2

Note: we have heard more about pleural effusion in the current trials, so

it will be interesting to see how this gets updated at this years ASH.

He spoke about other things in the works such as Vaccines and things, but

only briefly so. I think I'll get much more information at ASH.

We finished off by presenting Dr. Ravandi with a Moose so he could tell all

his friends he went Moose hunting in Canada.

I have to tell you this though, as I mentioned he had presented to a bunch

of oncs the day before, he mentioned he got much better questions from our

patient audience than from the docs that he presented to. He was very

impressed with our level of knowledge.

We thoroughly enjoyed his company.

Stay tuned for big news on more meetings coming in the future.

Cheers,

Cheryl-Anne