Phase 1 oncology trial designs

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.

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.

With multiple agents being tested, the complexity and need for precision of dose-finding studies both grow tremendously. In particular, special designs are needed for studies involving:. It is a Phase II, two-stage design with no control that rejects ineffective treatments early. The two stages are:. If the trial ends in the first stage, researchers may choose to explore other indications and dosing strategies.

By Premier Research. Rules or Models? Other specific types of statistical design include: Slope-sign design: Dose finding is directed based on the sine of the estimated slope of the dose-efficacy curve. Logistic design: Uses a dose-efficacy curve that follows a Bayesian logistic model.

Isotonic design: A non-parametric approach using isotonic regression. Local logistic design: Wherein the model for the dose-efficacy curve uses two adjacent doses. The two stages are: A small number of patients is enrolled. CP One way to shorten the testing time for a combination at phase 1 is by using an accelerated titration design.

If we know, based on either other drugs in the same class, preclinical data in animal models, or other studies, that the drugs are safe at certain dose levels, it may be possible to accelerate the titration, using 1 or 2 patients per cohort instead of the usual 3, and escalating the doses faster.

CTEP works with drug companies and academic investigators who provide preclinical data or data from phase 1 single-agent studies. Investigators may submit a letter of intent demonstrating a strong biological rationale why a combination approach might be superior to a single-agent approach.

If CTEP agrees, it will facilitate the partnership and provide funding for the clinical trial. CP If 2 drugs are being studied in combination, it is necessary to try to determine which is more biologically active.

If a drug is approved and known to be active in a particular tumor type, the dose of that drug should be kept constant at its known effective level. If another drug is known to enhance the first drug, it should be added slowly. The dose of the active drug will be fixed, and the dose of the enhancer will be titrated up in a phase 1 trial in order to find the optimal dosing level.

If excessive toxicity arises, the dose or doses will be reduced. CP The phase 1 trial determines the recommended phase 2 dosing for the combination.

In some cases, a phase 1 trial may detect toxicities that prevent investigators from proceeding with a phase 2 trial. Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Discov.

N Engl J Med. Dose-escalation models for combination phase I trials in oncology. In Phase I development, design properties are typically estimates of characteristics of the investigational drug, including the MTD, linearity of the compound, or the accumulation of the drug under repeated dosing. Other properties may be useful as well, such as expected or maximum sample size in an adaptive design and the probability of dosing at or above the MTD.

The characteristics are prospective in the sense that we cannot discuss these after the trial has been run: at the conclusions of the trial, the MTD was either exceeded or not. Early clinical development of oncology therapeutic agents presents unique requirements for biomarker strategies and implementation that may be addressed through early planning and preparation.

A primary goal in early studies is to ensure that patient samples and testing capabilities are sufficient to provide the needed data to support this analysis. Early trials are also often expanded to obtain early signs of efficacy and to guide selection of subsequent indications and target patient populations. Therefore, preparations may also consider exploratory biomarker analyses and early predictive biomarkers.

This increased emphasis on drug activity or pharmacodynamic data has introduced a greater requirement for early development and laboratory implementation of pharmacodynamic assays. These assays may be proximal to drug-target engagement such as a target occupancy assay, or may be more proximal or disease related such as a downstream signaling event or a change in patient physiology or disease condition.

Optimally, a chain of evidence will be established linking activity from target to disease.