RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Dose Escalation QuestionMy understanding is they have now dosed the first patient twice and they can keep dosing the same patient until they show DLT then they use the data and go back to design 1(traditional 3+3 design) thus less patients are unnecessary exposed to very low dosing and they save some time as well. This might explain why the second patient hasn't been dosed.
below is the original design 1 procedure.
"If none of the three patients in a cohort experiences a dose-limiting toxicity, another three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a dose-limiting toxicity, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six patients experience dose-limiting toxicities (ie, ≥33% of patients with a dose-limiting toxicity at that dose level). The recommended dose for phase II trials is conventionally defined as the dose level just below this toxic dose level.” scarlet1967 wrote: That's correct, my point was it looks like they can keep dosing the first patient until they show toxicity then they go back to original design with 3 to 6 patients will be dosed. If that's their approach it might be longer time than classic design before they move on to the second, third etc patients.
"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 (4). 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."
qwerty22 wrote: The trial expects 65 patients and part 2 accounts for 40 so that leaves 25 for dose escalation. I don't know how that fits with any of these designs.
I'm not worrying at all about the cancer program, it seems on track atm.
scarlet1967 wrote:
As per the company the study will use a modified rapid dose-escalation design as described by Simon et al. (1997). Looking through the article below they might stay with one patient only (not traditional 3+3 escalation design), doubling the dose until the patient shows DLT, which can reduce the duration of the trial etc.
“Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced(DLT) dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial accelerated phase.
The new designs described here appear to accomplish several objectives. They reduce the number of patients potentially undertreated. Some of these designs also reduce the duration of trials by doubling the dose until toxicity develops. These approaches also improve the information yield of phase I trials. They provide for estimation of the population distribution of the MTD and may also provide a statistical estimate of the degree of cumulative toxicity.”
https://brb.nci.nih.gov/techreport/AcceleratedTitration.pdf