The development of oncology drugs is a complex, multi-phase process, where safety, efficacy, and optimal dosing are determined progressively through clinical trials. The primary focus of Phase I oncology trials is to establish the safety profile of a new therapy and identify the Recommended Phase II Dose (RP2D) to carry forward to subsequent phases. To ascertain the RP2D effectively, Phase I trials are often split into two critical sub-phases, dose escalation and dose expansion.
Figure 1 below outlines the basic structure for determining RP2D with sequential dose escalation and dose expansion phases.
Figure 1: Simple Schematic of Phase 1 Study with Expansion Phase
What is Dose Escalation?
The dose escalation phase is typically the first step in a Phase I trial. During this phase, researchers focus on gradually increasing the drug dosage in small cohorts of patients to identify the maximum tolerated dose (MTD). The MTD is the maximal dose where the dose limiting toxicities (DLTs) do not exceeding a pre-specified limit. The decision to escalate the dose is typically guided by the “3+3” design or other advanced statistical models, such as Bayesian approaches, that consider prior data to determine the safest next dose level. This phase is crucial for determining the appropriate dose range and ensuring patient safety.
What is Dose Expansion?
The dose expansion phase is initiated once the MTD or a biologically effective dose has been established. The primary goal of dose expansion is to further evaluate the safety and preliminary efficacy of the selected dose across a larger, more diverse population. This phase allows researchers to explore the therapeutic potential in multiple patient subgroups, focusing on different tumour types or biomarker-defined populations to further explore the drug's therapeutic potential and inform the selection of the RP2D.
Table 1 below outlines the key differences between the dose expansion and dose escalation phases of Phase I oncology trials.
Table 1: Comparison of Dose Escalation and Dose Expansion Phases
|
|
Dose Escalation Phase |
Dose Expansion Phase |
|
Primary Objective |
Determine the maximum tolerated dose (MTD) |
Confirm safety at the selected dose, evaluate preliminary efficacy, and refine RP2D |
|
Patient Population |
Small cohorts of patients, typically 3-6 per dose level |
Larger cohorts with more diverse patient populations |
|
Dose Levels |
Multiple dose levels tested sequentially |
Single or a few dose levels tested simultaneously |
|
Decision Criteria |
Dose is increased until MTD or DLT is observed |
Assess if the selected dose is suitable for larger-scale studies |
|
Outcome |
Determine MTD or biologically effective dose |
Establish RP2D and assess early signs of efficacy |
More on the Rationale Behind Dose Expansion Phases
Before advancing to Phase II, it is essential to confirm that the RP2D (Recommended Phase 2 Dose) is both safe and effective for the intended patient population. This involves evaluating whether the RP2D demonstrates sufficient efficacy and considering if lower, less toxic doses might also provide similar therapeutic benefits[1]. This is where dose expansion phases play a crucial role.
Expansion phases allow researchers to gather additional data on pharmacokinetics, pharmacodynamics, toxicities, and other safety endpoints. Once a dose—or multiple doses—of interest has been identified, additional cohorts can be included to further explore these aspects and refine the definition of the Phase II study population[2]. These additional cohorts may have larger sample sizes or be stratified based on specific prognostic factors, enabling a more targeted evaluation and selection of the optimal patient groups for subsequent trials.
Regulatory Perspectives and Controversies in Dose Expansion Phases
From a regulatory standpoint, the FDA has not issued binding recommendations on the inclusion of dose expansion phases in Phase I oncology trials. While the FDA recognizes that expansion phases can provide valuable information on efficacy and a deeper understanding of pharmacokinetics (PK) and safety profiles, it also cautions against the potential risks, such as over-exposing patients and making premature inferences based on limited data[3].
The medical community is also divided on the use of dose expansion phases. Proponents argue that incorporating these phases can accelerate drug development timelines. However, critics raise concerns about the lack of scientific rigor, as these phases often lack a robust justification for sample size and are not always accompanied by a predefined analysis plan[4,5,6]. Moreover, without proper design and objectives, dose expansion phases may not yield meaningful insights.
Despite these concerns, the uptake of dose expansion phases has continued to grow. In 2006, only 12% of Phase I oncology trials included a dose expansion phase, compared to 38% in 2011[7]. This trend highlights the need for careful planning to ensure that these phases are designed to yield scientifically and clinically justifiable data. Properly justifying sample sizes and clearly defining objectives can help mitigate the risks and maximize the benefits, such as reduced overall costs and better resource allocation toward promising drug candidates[5].
Challenges in Statistical Validity and Population Selection for Dose Expansion Phases
When evaluating the validity of results obtained from dose expansion phases, it is often argued that large sample sizes are not necessary for assessing preliminary efficacy[1,8]. This viewpoint aligns with the majority of Phase I trials with expansion phases conducted in 2011[9]. However, this does not eliminate concerns about statistical validity. For instance, if multiple cohorts with small sample sizes are used and the primary outcome is Overall Survival (OS), it may be challenging to ensure that there are enough events in each cohort to achieve statistically robust results.
In simpler expansion studies with a single cohort, typically dosed at the RP2D determined during the dose escalation phase, these concerns are less pronounced. However, careful consideration must be given to the definition of the expansion phase population. For example, excluding participants with major protocol deviations or enrolling patients with specific cancer subtypes can significantly influence the results. This latter criterion—selecting specific cancer subtypes—is often employed in expansion phases if certain patient groups show a better response during dose escalation[6].
Ad-hoc selection based on apparent responses observed in small sample sizes can lead to misleading conclusions about efficacy. Small sample sizes increase the risk of observing false-positive results, where a perceived treatment effect is simply due to chance. To minimize this risk, expansion phase populations should be predefined and selection biases should be avoided whenever possible.
Evaluating the Role and Impact of Dose Expansion Phases
In 13% of clinical trials where the primary objective of the expansion phase was to further evaluate safety, the Recommended Phase 2 Dose (RP2D) was modified based on new findings from this phase. Moreover, 54% of these trials reported new toxicities not observed during the initial dose escalation phase[10]. This highlights the critical role that dose expansion phases can play in refining dose selection and uncovering additional safety concerns. Simulations have also shown that in 50% of trials, the Maximum Tolerated Dose (MTD) was not accurately determined during the dose escalation stage alone, necessitating further evaluation in an expansion phase[11].
A meta-analysis of 381 cancer drugs further supports the value of dose expansion phases, demonstrating that trials incorporating these phases had a higher probability of success in Phase II[8]. While this suggests that dose expansion phases can provide a more comprehensive safety profile and potentially prevent the failure of Phase II studies due to suboptimal dosing, it is important to consider the limitations associated with current Phase I trial designs.
Most Phase I trials utilize the traditional 3+3 design, which, as discussed in Quanticate’s whitepaper The Design of Phase I Oncology Studies, has several limitations in accurately determining the RP2D. If more advanced, model-based designs are more effective at identifying the appropriate dose, the necessity of a large-scale dose expansion phase becomes questionable. While obtaining a clearer picture of the drug’s safety profile is beneficial, extending the trial to perform a complex expansion phase—especially if it does not result in a change to the RP2D—could be viewed as unnecessary and resource-intensive. This is particularly relevant considering that some dose expansion phases are as complex and costly as the dose escalation phases.
Overall, while dose expansion phases can enhance our understanding of a drug's safety and efficacy, careful consideration should be given to their design, objectives, and whether they truly add value to the clinical development process.
Conclusion
In summary, incorporating a dose expansion phase in Phase I oncology trials can offer substantial benefits by providing additional insights into a drug’s efficacy, safety, toxicity, and pharmacokinetic profiles before progressing to a potentially costly and unsuccessful Phase II study. The key criticisms of dose expansion phases often stem from inadequate planning and a lack of statistical rigor, which can undermine the validity of the results.
However, even with an optimally designed dose expansion phase, it is crucial to ensure that the dose escalation phase is robust and well-structured. An expansion phase should not be used as a remedy for deficiencies in dose escalation design, such as poor dose assignments or incorrect RP2D determinations. Avoiding these pitfalls requires careful planning and expert guidance in trial design and statistical analysis.
Addressing these challenges early on is where Biostatistical Consulting can add value, ensuring that both the dose escalation and dose expansion phases are strategically designed to yield scientifically valid and clinically meaningful outcomes for your study.
If you feel a dose expansion phase may be suitable to help with a Phase I oncology study that you are designing, the Quanticate Statistics Department would be delighted to discuss your requirements and provide advice about possible ways to increase the chance of a successful study. For more information please submit an RFI.
References
[1] - Roychoudhury, S., & Lahiri, S. (Eds.). (2018). Statistical Approaches in Oncology Clinical Development: Current Paradigm and Methodological Advancement. CRC Press.
[2] – Boonstra P.S et al (2017). Statistical controversies in clinical research: building the bridge to phase II—efficacy estimation in dose-expansion cohorts. Annals of Oncology
[3] - Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics Guidance for Industry (2018) https://www.fda.gov/media/115172/download [Accessed 16AUG2019]
[4] - Percy Ivy, S. et al (2010) Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee. Clinical Cancer Research.
[5] - Iasonos, A., & O'Quigley, J. (2015). Clinical trials: Early phase clinical trials-are dose expansion cohorts needed?. Nature reviews Clinical oncology.
[6] O’Quigley, J. & Iasonos A. (2014). Dose expansion cohorts in Phase I trials. Memorial Sloan-Kettering Cancer Center, Dept. of Epidemiology & Biostatistics Working Paper Series
[7] Manji A et al (2013). Evolution of Clinical Trial Design in Early Drug Development: Systematic Review of Expansion Cohort Use in Single-Agent Phase I Cancer Trials. Journal of Clinical Oncology.
[8] - Bugano, D. et al. (2017). Use of expansion cohorts in phase 1 trials and probability of success in phase 2 for 381 anticancer drugs. Clinical Cancer Research.
[9] – Dahlberg, S.E. et al (2014). Evaluation of Statistical Designs in Phase I Expansion Cohorts: The Dana-Farber/Harvard Cancer Center Experience. Journal of the National Cancer Institute.
[10] – Wages,N et al (2018). Design considerations for early-phase clinical trials of immune-oncology agents. Journal for ImmunoTherapy of Cancer.
[11] – Hansen A., & Razak A (2014). The benefits of including expansion cohorts in Phase I oncology clinical trial design. Clinical Investigation.
