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Old 12-05-2007, 04:17 PM   #21
runtolive
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Join Date: Nov 2007
Posts: 210
sarah...
Rationale
Trastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody-drug conjugate (ADC) in development for HER2-positive breast cancer (BC). T-DM1 is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. Focusing such chemotherapeutic agents on tumor cells via high-specificity monoclonal antibodies that bind unique and/or over-expressed cell-surface tumor antigens is intended to improve the therapeutic window for such agents, allowing their potential to be applied to the clinic.
DM1 binds to tubulin competitively with vinca alkaloids, but 20-100 times more potently than vincristine. Its parent molecule, maytansine, has induced responses in patients (pts) with breast and lung cancer, with principal adverse events (AEs) of nausea, vomiting, diarrhea, and sensory neuropathy. The stable MCC linker molecule was engineered to potentially enhance the therapeutic window of DM1 by improving exposure to T-DM1 and minimizing exposure to free DM1. T-DM1 is the first ADC with an MCC linker in clinical trials.
T-DM1 binds to HER2 with affinity similar to that of T and is internalized via the normal ongoing HER2 internalization process. T-DM1 has activity in both T-sensitive and T-insensitive HER2+ BC xenografts; its principal preclinical AEs were reversible transaminase (TA) elevations, reversible decreases in platelets, and neuropathy.
Objectives
This ongoing first-in-human phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV to pts with advanced HER2+ BC who have progressed on a T-containing regimen.
Results
Nineteen pts (median age 50 (range 35-70); all PS 0-1); median number prior chemo regimens 8 (range 2-18) have received 83 doses of T-DM1 at 6 dose levels (0.3-4.8 mg/kg) on a q3 wk schedule. Related mild-moderate AEs include TA elevations (grade (gr) 1, 4 pts; gr 2, 1 pt), thrombocytopenia (TCP; gr 1, 5 pts), fatigue (gr 1, 5 pts; gr 2, 1 pt), anemia (gr 2, 2 pts), and peripheral neuropathy (gr 1; 1 pt). Related gr 3-4 AEs have been limited to rapidly reversible TCP (gr 3, 1 pt; gr 4, 2 pts). There has been no cardiac toxicity. T-DM1 clearance decreased with increasing dose as predicted by preclinical modeling. Four of 16 pts treated at or below the MTD have had partial responses; three are confirmed and ongoing after 1.7-5.5 months.
Conclusions
The MTD of T-DM1 given IV q3 wks is 3.6 mg/kg; TCP was dose-limiting at 4.8 mg/kg. At the MTD, gr 2 AEs related to T-DM1 have been infrequent and manageable. T-DM1 PK is consistent with q3-week dosing. Objective tumor responses have been observed at doses at or below the MTD. Phase II trials in advanced HER2+ BC are being initiated; weekly dosing is also being explored.
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Old 12-08-2007, 02:10 AM   #22
sarah
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Join Date: Sep 2005
Location: france
Posts: 1,643
This sounds like a very hopeful drug. thanks for making us all aware of it.
I know that for Lyme disease they sometimes gave the patient a slight dose of malaria and then treated them so that way they could "get into the brain" and destroy the Lyme disease.
Sometimes cures seem so close but still so far away.
thanks to all of you. So nice to have such a wonderful community of friends to turn to for help, particularly when you feel lost and worried.
Our friend is courageous and a fighter, so that's good.
thanks
hugs and love
sarah
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Old 12-21-2009, 02:45 AM   #23
charlotte
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Join Date: Apr 2006
Posts: 131
Re: when tykerb/xeloda don't work, what next?

I have been on tykerb+xeloda for about a year or so.
I have seen little if any mets disappearing. I was wondering if 5fu added to the mix would help.. This is my thoughts....Has anybody tried this combo??any suggestions.
It is so depressing to look at my chest.. It is red, rashy, some (afew) have what looks like it is infected. My whole chest (with the exception) of a few areas is now complety
covered in breast cancer.I had a pet scan,done and it says..." no signs of cancer".Tell that to my chest..!!
I think this is so sad to look down at my chest and see this "mess". It was bad enough to get the inflammorty so far, I have taken gemzar,taxol, 5fu cream, herceptin (4doses) heart cannot handle it.. my ejection fraction is now 25%to 30%.
xeloda, tykerb.I guess it is because I have to look at at least once a day.
radiation treatments.. This is my thoughts....
. , My whole chest (with the exception) of a few areas is now complety
covered in breast cancer.I had a pet scan,done and it says..." no signs of cancer".Tell that to my chest.. so far, I have taken gemzar,taxol, 5fu cream, herceptin (4 doses)
xeloda, tykerb.I guess it is because I have to look at at least once a day.
Thanks for asking about Luke.. He is steadly improving .. Here is the rub, the stronger he gets, the further on down the list of people needing a lung transplant, who are "worse" than him.He gets bumped on down to another level.
Ironic isn't it???
He had a lung waiting at Shands, but was too sick to have the procedure.. Strange isn't it??? The better he gets along, the Lower he goes down on the "waiting" list.
He is still at Shands and they are talking like it will be sometime before he comes off the inactive list , to an
active slot.
I feel like I am going to eventually lose it.. maybe, I already have, and just don't know .?
this will be my first Christmas in 28 years, we have been married. That we will not be together. I know other people on this site , with problems worse than mine.. I guess I need to vent.. sorry.....Charlotte
I am not trying to be depressing, but it is hard to not be, with all the stuff going on.

Last edited by charlotte; 12-21-2009 at 03:30 AM.. Reason: typos
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Old 12-23-2009, 02:33 PM   #24
Ellie F
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Join Date: Feb 2009
Posts: 1,526
Re: when tykerb/xeloda don't work, what next?

Hi Charlotte
What about a T_DM1 trial? i know these are difficult to find but Vickie H was suffering skin mets badly and managed to get on this trial and last posting suggested it was working as the mets were receeding
Ellie
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