Clinical trials serve as a pivot point for developing new oncology drugs and the timely delivery of safe and efficient treatments to patients. Adaptively designed and biomarker-driven evaluations of molecularly targeted agents and immune therapies in chosen patient subsets have replaced traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations in clinical trials.
The scientific, methodological, practical, and patient-centered factors that transform clinical trials will be covered in this review. Creating a framework for next-generation clinical trials that strikes the ideal balance between operational effectiveness, scientific impact, and patient value is proposed as a call to action.
Clinical Trial in Oncology
Patients are typically categorized in oncology according to their primary cancer and stage of the illness, and randomized controlled trials are carried out for each patient population to develop standard therapies.
This viewpoint has historically served as the foundation for developing cytotoxic drugs. Still, scientists have better understood the cellular and molecular mechanisms underlying cancer cell growth and progression in recent years.
The division of specific tumor types into various subtypes was made possible by the discovery of molecular markers or genetic mutations. The development of oncology drugs is moving from cytotoxic agents to molecularly targeted agents, which act only on cancer cells.
Clinical trials conducted by Contract Research Organization (CRO) design methodologies in oncology have advanced with the science underlying therapeutic interventions, resulting in a significant paradigm shift in creating novel cancer therapies.
Rule-Based vs. Model-Based Study Design for the First Phase
Phase I trials are typically created to evaluate a novel drug or treatment’s safety and maximum tolerated dose (MTD). Oncology phase I clinical trials are generally small, single-arm, open-label, sequential dose-escalation studies with suitable performance status patients whose cancers have progressed despite standard treatments.
Avoiding overexposing patients to subtherapeutic doses while maintaining safety and rapid accrual is the guiding principle for dose escalation in Phase I trials. Numerous methods are currently available for Phase I trials, from traditional simple rule-based designs like the 3 + 3 design to sophisticated computational models utilizing Bayesian algorithms.
The simplicity of rule-based designs, like the 3 + 3 design, leads to their widespread use in most Phase I trials despite statisticians recommending the adoption of model-based designs.
The need for a tailored design approach has grown due to the introduction of new targeted therapies where the fundamental presumption of a linear relationship between dosage and toxicity may need to be revised.
There needs to be an agreement on the best design for Phase I studies, necessitating a review of each design’s benefits and drawbacks.
Three categories of frequently used designs for Phase I studies are established: traditional rule-based designs, dose-escalation designs guided by pharmacokinetics, and model-based designs.
Design of the Phase II and III Study
A novel agent or combination regimen’s tumor response rate is typically assessed in Phase II trials in oncology settings using a single-arm study design to determine whether further testing in a Phase III study, which establishes clinical efficacy, is necessary.
Oncology Phase II studies with a single arm typically employ one- or two-stage designs. The most straightforward designs are single-stage ones that focus on one group (single-arm) of patients (such as the A’Hern design).
Two groups of patients are separated into two-stage formats (or stages). After stage one, an interim analysis is performed to determine whether stage two should occur.
The most popular single-arm Phase II design in oncology drug development is Simon’s design. This design includes the option to stop for futility after the first stage. It aims to reduce the largest sample size (minimax design) or the expected sample size under the null hypothesis (optimal design) compared to other designs with equal significance levels or power.
Phase II clinical trials are designed using a different method, the Bryant and Day design, which takes toxicity into account. Whether to conduct an uncontrolled single-arm Phase II with a tumor response endpoint or a controlled multiple-arm randomized Phase II with a survival (or comparable efficacy parameter) endpoint is hotly debated.
When transitioning from Phase II to Phase III trials for novel molecularly targeted drugs, it’s important to consider emerging variables and advanced elements such as adaptive trial designs and biomarker-based approaches.
Wrapping Up
Over the past few decades, significant improvements in the clinical trial design methodology and molecular understanding of cancer have occurred. The use of master protocols has recently increased significantly, and agnostic-histology approvals are expected to continue to rise.
Researchers should keep developing novel trial designs, early-stage decision-making strategies, and early selection of candidate drugs with a high chance of success to keep up with these changes.
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