Phase I trials classically represent first-in-human studies with the primary goals of :
describing drug toxicities,
describing the pharmacology of the drug (pharmacokinetics and sometimes pharmacodynamics)
identifying an appropriate dose for phase II studies.
With cytotoxic agents, an assumption has always been made that the higher the dose, the greater the likelihood of drug efficacy. This assumption was based on the log-cell kill hypothesis propounded by Skipper and colleagues, which is discussed briefly below:
Dose-response relationships in cancer chemotherapy
Skipper and colleagues proposed a “steep” dose-response relationship in cancer chemotherapy, referring to a linear relationship between drug doses and fractional cell kill. This concept dated back to the 1960s when Skipper and Schabel predicted a log cell kill model for antineoplastic drugs. In this model, the relationship between tumor cell kill and drug dose was exponential, with the number of cells killed by a given dose of drug being proportional to both the dose of the drug and the number of cells exposed to the drug. The steepness of the dose-response curve implies that a disproportionately high number of cancer cells are killed when drug doses are minimally increased. Thus, the higher the dose, the more effective the drug. This is in contrast to most other classes of therapeutic agents, which exhibit a sigmoidal dose-response relationship, with a linear relationship between dose and response over a relatively narrow range of drug doses. The plateau in this traditional curve suggests that after a certain threshold dose, further increments do not lead to an increased response. Toxicity and Efficacy
In addition to the relationship between dose and anti-tumor response, cytotoxic agents also exhibit a dose-toxicity relationship. Thus, dose-related toxicity is regarded, as a surrogate for efficacy. The highest safe dose is assumed to be the one most likely to be efficacious. These assumptions underlie the design of phase I studies. Doses of drugs are escalated until the achievement of significant, but reversible, toxicity. These toxicities that preclude further dose escalation, represent the dose-limiting toxicity (DLT). DLTs are defined in advance in phase I trials. The maximum-tolerated dose (MTD) is defined as that dose producing a certain frequency of DLTs within the treated patient population. The MTD is either taken as one dose level below the highest toxic dose (ie the DLT dose), in which case the MTD is the recommended phase II dose; or the MTD is sometimes taken as the DLT dose, in which case the dose level below the MTD is the recommended phase II dose. How is the starting phase I dose selected ?
Initial toxicologic studies are performed in rodents (typically mice) and another large species (typically canines). In the mice studies, a dose at which approximately 10% of the mice die (the murine LD10), is defined. One tenth of this murine equivalent LD10 (0.1 MELD10), expressed in milligrams per meters squared, has historically been a safe starting dose in humans when toxicologic studies in a second species (eg, rat, dog) do not show substantial differences in the dose-toxicity relationship. Patients are accrued in cohorts of three, and escalating the dose according to a modified Fibonacci sequence in which dose increments become gradually lower as the MTD is approached(example, dose increases of 100%, 65%, 50%, 40%, and 30% to 35% thereafter). The dose escalation is continued in cohorts of three patients until typically, 2 DLTs are seen in a maximum of 6 patients. Ethical Issues
i) Substantial numbers of patients are treated at non-therapeutic doses. It has been calculated that the majority responses in phase I studies occur within 80% to 120% of the recommended phase II dose. These considerations raise ethical pressures to treat fewer patients at the initial dose levels...