HER2 Support Group Forums - View Single Post - when tykerb/xeloda don't work, what next?

runtolive · 12-05-2007, 04:17 PM

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.

12-05-2007, 04:17 PM	#21
runtolive Senior Member 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.