Traditionally, phase 1 oncology trials have relied on a standard 3+3 dose escalation design to achieve the objective of defining a recommended phase 2 dose (RP2D). However, statistical simulations have shown that as few as one in three trials using the 3+3 design succeed in identifying the maximum tolerated dose. Concerns have also been raised that this method of dose escalation may result in a high percentage of patients being treated at subtherapeutic doses. With the advent of molecularly targeted agents (MTAs) and immunotherapies, which have toxicity profiles that are distinct from those of cytotoxic agents, we are increasingly seeing innovative phase 1 trials that may be better suited to dose-finding studies of novel therapeutics.
Evaluating Safety in Phase 1 Studies
The purpose of a phase 1 trial is to obtain reliable data on the safety, pharmacokinetics, and mechanism of action of a drug. With cytotoxic agents, dose-finding studies focus on determining the highest dose with acceptable toxicity and toxicity is measured as a binary endpoint referred to as dose-limiting toxicity (DLT). Most dose-escalation methods were developed with the assumption that toxicity increases with dose in a monotonic fashion. As such, R2PD has traditionally been synonymous with the highest safe dose, or maximum tolerated dose (MTD), identified in a phase 1 trial.
A typical dose-escalation phase 1 study selects a safe starting dose based on in vitro and in vivo preclinical data. The dose is increased incrementally for assigned patient cohorts until a pre-specified endpoint — generally, DLT — is reached. However, standard dose-escalation methods may not suit the development of MTAs and immunotherapies, as these agents may not produce DLT and their side effects may not be dose-dependent. As such, the endpoint for phase 1 studies of MTAs and immunotherapies may be the optimal biological dose (OBD), rather than an MTD.
Selecting a safe starting dose must be balanced against the proportion of patients treated at sub-therapeutic doses. This is especially important for agents that demonstrate minimal toxicity in preclinical testing or for drugs that are unlikely to ever reach MTD. If a range of biologically active doses could be predicted from preclinical models using pharmacokinetic (PK) or pharmacodynamic (PD) endpoints, this information could be applied alongside preclinical toxicology data to inform starting dose decisions. This approach has the potential to reduce the number of dose escalations while preventing patients from being treated at overly toxic doses that lack incremental biological activity.
Studying Drug Combinations in Phase 1 Studies
Combination therapy is becoming more common in early-phase studies of immuno-oncology products. Unlike monotherapies, the MTD for a combination therapy is not a single number. Instead, it is a space on the dose curve between the two drugs, and the RP2D is the point within that space which is predicted to give maximum tumor growth rate inhibition.
When a novel MTA is combined with a cytotoxic agent, a standard multi-arm trial dose escalation scheme may be appropriate since the dose of chemotherapy is fixed to one or a few possible doses. The situation is more complicated when combining two novel MTAs, both of which can have several doses. In addition, the safest and most effective doses of each MTA may be different in the combination setting than when used as monotherapy.
Selecting a Study Design
Investigations of immuno-oncology products that target tumor mutations may be well-suited to a basket study design. While traditional clinical trials focus on a particular cancer type, basket studies are concentrated on a specific mutation found in the tumor, regardless of where the cancer originated. As such, if the interest is in studying the effect of a specific treatment within a particular biomarker-positive group of patients, a basket study may be an appropriate option.
Another study design to consider is an adaptive dose escalation design, where a single dose regimen is used to determine MTD before switching to a multiple dose regimen to determine RP2D. Adaptive dose escalation studies may include multiple cohorts and multiple tumor types and are designed to take advantage of emerging knowledge by allowing modification to key trial parameters according to planned rules.
 Reiner E, Paoletti X, O’Quigley J. Operating characteristics of the standard phase I clinical trial design. Comput Stat Data Anal 199;30(3):303-315.
 Simon R, et al. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 1997;89(15):1138-1147.