scarlet1967 wrote: Both Gettysburg Cancer Center and MD Anderson Cancer Center are still recruiting patients.
https://www.clinicaltrials.gov/ct2/results?cond=&term=TH1902&cntry=&state=&city=&dist=
https://www.mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2021-0030.html
I am going to revisit the schedule of dose escalation, as per the trial’s description the study will use Accelerated Titration Designs for Phase I by Simon et al.(1997) which has 4 designs:
“ Design 1 is the standard 3+3 Dose steps are defined by a modified Fibonacci series in which the increments of dose for succeeding levels are 100%, 67%, 50%, and 40%, followed by 33% for all subsequent levels. 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. Designs 3 and 4 also use only one patient per cohort during the early stage of the trial, but they incorporate more rapid dose escalation by using double-dose steps during this stage. With design 3, the single-patient-cohort stage of the trial also terminates when one patient experiences first-course DLT or two patients experience first-course grade 2 toxicity. Design 2 treats one patient per dose level until one patient exhibits DLT or two patients exhibit grade 2 toxicity during their first course of treatment. At that time, the escalation plan switches to design 1. That is, two additional patients are accrued at the dose that triggered the switch, and three to six patients are treated in that and each subsequent cohort. This approach offers the possibility of speeding up the trial and reducing the number of patients assigned to low doses. It uses the first instance of first-course DLT to trigger the switch as proposed by Storer. It also uses first-course grade 2 toxicity to provide an added element of caution. We use the second instance of grade 2 toxicity for practical reasons, since it is often difficult to determine whether a grade 2 toxicity is drug related in a heterogeneous population of very ill patients. With design 4, this accelerated stage terminates when the first instance of DLT or the second instance of grade 2 toxicity is observed in any course of treatment. In either case, after the rapid escalation stage terminates, subsequent cohort sizes are three to six patients and single-dose escalation steps are used as in design 1.”
The reason for choosing the modified rapid dose escalations is:
“Although most patients who participate in phase I trials hope to obtain therapeutic benefit from promising new experimental treatments, few achieve this objective. Whereas most patients would not have derived benefit from drugs studied in phase I trials, even if treated at the maximum tolerated dose (MTD), treating patients at substantially lower doses is likely to further reduce whatever chance for benefit might exist. A second problem with current designs is that phase I trials may take a long time to complete, especially when the starting dose is far below the MTD (3). Current phase I trials also provide almost no information about variability among patients in the dose that can be tolerated without dose-limiting toxicity (DLT) or about whether there is evidence of cumulative toxicity.”
https://brb.nci.nih.gov/techreport/AcceleratedTitration.pdf
So they will dosing one patient per dose until one patient shows DLT (dose limiting toxicities) at that time, the escalation plan switches to design 1.
Absent any toxicity they started with 30mg/m2 and doubled the dose for the first two cycles by May 3 they would be at 120mg/m2 then applying modified Fibonacci dose escalation scheme (67%, 50%, 40% and 33%) forth cycle would be at a dose=120x1.67%=200mg/m2 May 24, fifth cycle 200mg/m2x1.5=300 mg/m2 June 14.
Sixth cycle 300mg/m2x1.4=420mg/m2 July 5, seventh Cycle 420mg/m2x1.33=559mg/m2 July 26. The company said they need one fourth of PDC dosages versus docetaxel alone to have therapeutic effects even bypassing that as per current recommendation docetaxel can have therapeutic effect starting at or just below 100mg/m2. So theoretically if no toxicity at and above the forth cycle their PDC will have progressively more therapeutic effect than docetaxel.