Sox - Older chemo drugs had to start at the tiniest of doses. This drug started at a specific percentage of the highest tolerated animal dose, also a tiny dose, but newer novel cancer drugs are not anything like the old chemotherapeutic agents and don't start at as scant a dose. This drug did not start at an unusually high level - the company, like all companies, had to follow standardized methodology to derive their safest starting dose.Here is the formula used in phI novel agent trials - I have posted this at IHub and here a few times - mainly just to show people that there is a standardized approach to these trials and that things like a 100% increase between cohorts 1 and 2 does not mean large increase in dosage and doesn't mean enything truly special is happening - such an event is just the formula of this kind of trial - nothing special about CTIX's starting dose and increases: Here is the formula for deriving starting dose of novel agent: (source of this info is: Phase I Clinical Trial Design
Lawrence V Rubinstein, PhD*
Richard M Simon, DSc*
Biometric Research Branch, National Cancer Institute
6130 Executive Blvd, Suite 8130, MSC 7434
Bethesda, MD 20892-7434)
The first problem in a phase I trial is deciding on a safe, but not overly conservative, initial dose for the trial. If the agent is new to clinical testing, this must be based on animal studies. It has been determined that the dose (defined in mg per meters squared of body surface area) associated with 10% lethality in mice (MELD10) can be predicted to be roughly equivalent to the human MTD 18. This approach is derived from the concept of “allometric scaling” 15, 25. Toxicity as a function of body weight or surface area is assumed to be roughly constant across species. The initial dose for the phase I trial is taken to be 1/10 the MELD10 or, if smaller, 1/3 the LD10 (associated with 10% lethality) in the beagle dog 23. The use of a second species has been shown to be necessary, since in approximately 20% of approximately 90 reviewed drugs, mouse data alone was insufficient to safely predict the human MTD 2. American investigators generally use the dog as the second species, while European investigators generally use the rat, with equivalent safety 2.
Standard phase I design
The “standard” phase I design utilizes a set of decreasing “Fibonacci” dose level increments proposed by Schneiderman 32, and currently taken to be 100%, 67%, 50%, 40%, and 33% thereafter 10. These increments are added to each dose level to give the succeeding level. In other words, the second dose level is 100% greater than the first, the third is 67% greater than the second, and so forth. The purpose is to allow more aggressive dose escalation for the initial levels, which are expected to be sufficiently removed from the MTD for this to be safe. If the MELD10 accurately predicted the human MTD, only 5-6 such dose escalations would be necessary to complete a “standard” phase I design. Unfortunately, this is often not the case 27.
The “standard” rule governing dose escalation from one level to the next relies on no assumptions concerning the shape of the dose-toxicity curve or the potential for cumulative toxicity, and therefore the decision to escalate to the next dose level is based solely on toxicity results from the first course administration of the current level. The dose escalation rules (Table 1) proceed as follows, escalating in cohorts of 3-6 patients per dose level 35. Three patients are treated at the current dose level. If at least 2 patients are observed to have DLT, the prior dose level is defined as the MTD (unless only 3 patients have been treated at that level, in which case it is the tentative MTD). If 0 of the 3 patients are observed to have DLT, the dose level is escalated one step for the next cohort of 3 patients, and the process continues as above. If exactly 1 of the 3 patients treated show DLT, 3 additional patients are treated at the current dose level. If none of these additional 3 patients show DLT, the dose level is escalated for the next cohort of 3 patients, and the process continues as above; otherwise, the prior dose level is defined as the MTD (unless only 3 patients have been treated at that level, in which case it is the tentative MTD). A tentative MTD becomes final when a total of 6 patients are treated with less than 2 showing DLT.
