Oncology Phase 1 Trials
White Paper

This IQVIA White Paper provides a comprehensive scientific review of Phase I trials in oncology, and highlights best practices and operational recommendations for their successful delivery. Early-phase studies, which introduce an investigational new drug into human subjects, represent a challenging first step in a new drug’s clinical development program. They are the bridge between basic science and clinical development, and provide pivotal information to select the right drug at the right dose for the right patients to be investigated in the subsequent phases of clinical development.


In the past few years, the landscape of early drug development in oncology has changed substantially. With the elucidation of the full sequence of the human genome and the latest breakthroughs in molecular biology and immunotherapy, very specific targeted therapies have been tailored to the specific pathophysiology of different types of cancers. Under the old model, investigational drugs were tested in a Phase I trial with a small, heterogeneous patient population to identify a safe dose before moving into disease-specific, Phase II protocols to test the antitumor activity. Today Phase I protocols are increasingly incorporating preliminary evaluation of anti-tumor activity and the selection of the cancer population more likely to be targeted by the new drug. Study designs include a dose escalation cohort to determine the maximum tolerated dose (MTD) of the optimal biological dose (OBD), followed by a dose expansion cohort with narrower eligibility criteria with focus on specific biomolecular features to confirm the recommended Phase II dose (RP2D) and to obtain preliminary evidence of the anti-cancer efficacy in selected patient subgroups.

Studies conducted in Phase I typically involve one or a combination of the following aspects3:

  • Estimation of initial safety and tolerability of single or multiple dose administration. This helps to determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the expected adverse reactions profile.
  • Pharmacokinetics to characterize the drug’s absorption, distribution, metabolism and excretion, including evaluation of special populations such as patients with hepatic or renal impairment, elderly and pediatric populations, and ethnic groups, and evaluation of drug-drug or drug-food interaction.
  • Assessment of pharmacodynamics, with development of pharmacokinetic/pharmacodynamic model(s) relevant to the drug blood levels in response to drug administration (pharmacokinetics/ PD studies). In this setting, pharmacodynamic data can provide early estimates of activity and potential efficacy.
  • Early measurement of drug activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective.
  • Comparative bioavailability, bioequivalence, and pharmacodynamics studies can be performed as early phase study to assess modified release dosage forms, pharmaceutical equivalents, or pharmaceutical alternatives.



There are many possible designs for early phase trials, and each has its strengths and weaknesses. Design properties are the statistical characteristics of the trial designs, and these are typically expressed in terms of frequentist properties. All statistical properties of trial designs are prospective, meaning that they look forward to future possible outcomes; indeed, trial properties are characterizations of the process of the trial itself, under assumptions of biological response to the dose stimulus. 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.

In this section, the following properties will be discussed:

  • Probability of exceeding MTD
  • Linearity
  • Accumulation


Early clinical development of oncology therapeutic agents presents unique requirements for biomarker strategies and implementation that may be addressed through early planning and preparation. These requirements may be viewed through the lens of the five R’s proposed by authors from AstraZeneca.21 The five R’s include using biomarker strategies to ensure that the right target, tissue, safety, patient and commercial potential are demonstrated through the clinical development program. In early development, the accepted focus is on safety and drug dosage including PK/PD analysis. 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.

Drug development practices in early development are moving away from the common practice of MTD to dosage linked to actual drug activity and patient impact such as BAD (biologically active dose), MABEL or NOAEL. 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. However, this is often difficult to obtain due to technical or specimen access limitations. Generally, any evidence from a subset of patients along this chain will be sufficient to demonstrate drug activity and guide dose along with preclinical and PK results. It is most important that the assays be developed and validated at the testing labs well before the start of the first-in-human studies and that sites are selected to support specimen collection and any processing required for the PD testing.



Each Phase I protocol has unique aspects which need to be analyzed and reviewed to make sure the strategy is appropriately set up to achieve the trial objectives.


Phase I trials with a cohort management component shall be carefully managed for the success of the trial. The key factor is to ensure a proper communication plan is in place with the inclusion of all the relevant stakeholders.

A cohort management plan allows the right procedures to be in place to ensure timely recruitment during the escalation part and also that each site has their allocated slot availability. Proper organization and planning of the Cohort Review Meetings allows minimization of the “white space” between cohorts, which translates into a higher speed of the overall trial conduct as well as data integrity and quality.

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