scarlet1967 wrote:
The DLT is at grade 3 or above, the toxicity is graded from grade 1 to 5.
Apart from 5( lethal consequences) all other grades are reversible hence the higher grades the more need of intervention, treatment and longer recovery. At the end of each cycle patients are reviewed for safety data so one can presume if there are any toxicity it will be detected there and then.
The below is a repeat of what quartly posted earlier.
As for MTD at any dose level if grade 3 toxicity is shown the MTD will be the previous lower dose. At any level
if 2 or more patients of a group of 3 show DLT the MTD will be the previous lower dose, if 2 or more patients of a group of 6 show DLT again the MTD will be the previous lower dose.
In May this year FDA initiated project Optimus, they try to move away from MTD as a working dose for trials due to adverse effects from high dosage.
To me the company needs to find an effective and safe dose as a working dosage going into phase 2 and beyond so although no DLT or DLT at whatever level as long as they have a good therapeutic window they might set a cut off target to make sure no one throughout the trial shows grade 3 or above toxicity.
The fact that as mentioned earlier the part1 phase 1 can take longer into fall has nothing to do with company trying to keep dosing patients with higher dosages but as many mentioned the process can take longer as there could be some back and forth in dosing depending on whether they see DLT during process.
This is the grading chart.
Adverse-Effects
Traditional 3+3 after the DLT is observed in first two or more cycles.
“1. Traditional 3+3 Design The traditional 3+3 dose-escalation design starts off by treating three patients at a conservative low dose. If no dose-limiting toxicities (DLTs) are observed, the trial proceeds to the next higher dose with three new patients. If one DLT is observed among the previous three patients, three more patients are treated at this dose. If no DLTs are seen among these three patients, the study moves on to the next dose. If two or more DLTs are found among the six patients, then the maximum tolerated dose (MTD) is defined as the previous dose. Likewise, if two or three out of three patients experience DLTs at any level, the previous dose becomes the MTD. This continues until an MTD is defined.”
qwerty22 wrote:
All sorts of grade 3 and beyond toxicities. Just bare in mind this is a very technical, defined process designed just to find a working dose. It's not really defining the full safety profile of the drug, that comes later, although I guess it's a pointer to that. I read this 3+3 MTD process typically leads to a situation where the drug gives grade 3+ events in 40-70% of patients in the clinic. As Scarlett discovered there is concern at the FDA this method is leading to too toxic drug doses.
palinc2000 wrote: At what point do they determine that MTD has been reached,,,How is toxicity defined? Is there a time factor involved,,,?Can toxicity be reversed after a a few days .....?