RE:RE:RE:RE:RE:RE:RE:RE:RE:Best Case Scenario This is my guess. They started the trial in the end of last March just short of 10 months ago. Initially we thought each cycle takes 3 weeks and then the company clarified that it takes another approximately 3 weeks for collection of data before moving on to the next higher dosage, absent any additional mortalities they would have enough time for 6 or 7 cycles .They dosed one patient at a time starting with 30mg/m2 then 60mg/m2, 120mg/m2, 200mg/m2, 300mg/m2, 420mg/m2, 560mg/m2, 745mg/m2 etc. absent any DLT. They keep escalating the dosage on single patients until there is a DLT, they do not go to lower dosage if there is a DLT event among single patients but move on to groups of 3 and later on 6 patients.
If they are still dosing single patients absent mortalities it means they are already at 560mg/m2 and no DLT event which is good and bad news. Good news is the fact the drug has been tolerated at those rather high dosages so it has been internalized in to cancer cells and bypassed the efflux. Again by definition the Docetaxel resistance is limiting intracellular drug concentration, less effect of the taxane due to alternative growth pathways or apoptotic escape and less stabilizing effect on microtubules so at that approximately 2.5 times of the MTD for Docetaxel alone this could most probably mean they could by pass the Docetaxel resistance which is one of main issues for many if not all cytotoxic agent. The bad news is we have to wait a bit longer for the MTD/RPD2. I think as long as they are dosing one patient at the time if true it doesn’t matter how many clinics are running the trial because it is still one single patient. As juniper mentioned if they are lining up patients now it is also good news because the remaing cycles will have less issues with the enrollment and there is an element of confidence re their results/data so far. Once they move to those groups of patient depending on DLT events it will be another few rounds of cycles, how many I don’t know but although it is not guaranteed MTD starting at 560mg/m2 or possibly higher on the groups would be a good darn start. These are possible scenarios as per Accelerated Titration Design when groups of patients are enrolled so it is data driven and the duration can vary depending on DLT events.
“Three patients are usually treated at a dose level and observed for acute toxicity for one course of treatment before any more patients are entered. If none of the three patients experience DLT, then the next cohort of three patients is treated at the next higher dose. If two or more of the three patients experience DLT, then three more patients are treated at the next lower dose unless six patients have already been treated at that dose. If one of three patients treated at a dose experiences DLT, then three more patients are treated at that same level. If the incidence of DLT among those six patients is one in six, then the next cohort is treated at the next higher dose. In general, if two or more of the six patients treated at a dose level experience DLT, then the MTD is considered to have been exceeded, and three more patients are treated at the next lower dose as described above. The MTD is defined as the highest dose studied for which the incidence of DLT was less than 33%.”
Now if you recall the project optimus by FDA is encouraging the sponsors to go easy on their MTD, I believe since the company is approaching this trial very cautiously with the extra time spent between the cycles collecting PK data and sortilin expression among others they would not move to those higher dosages if there were any meaningful risks identified during single patients’ enrollment as they could just called it in and use their MTD of preference moving on to the groups. The CMO is speaking in two different events in April and May which tells me the trial has been progressing well so far regardless of where their MTD ends up being which takes me to what I suggested before their MTD could end up at decent tolerated levels since the starting dosage is rather high in the groups of patients.