Pitfalls and Promises in Early Phase Oncology Trials

Conventional oncology trials can be flawed, costly, and experience high error rates. In addition, making improvements in cancer treatment can also be severely compromised by the rising price, time and number of participants required to enable traditional oncology trials to be conducted. Better cumulative decisions in early phases of development could lead to a greater chance of clinical success, as the correct dosage can be identified and tested in the right patient populations for the right early indicator.

In this article, we delve into the current and future aspects of early-phase oncology trials.

The Evolution of Phase 1 Oncology Trials

The medical inventory for treating cancer has grown quickly with the introduction of molecularly guided and immuno-oncological agents. Sustained positive results seen in patients with advanced cancers when such agents have been used, brings promise that successful new treatments could be implemented rapidly. This, in turn, has prompted us to rethink our existing early phase prototypes for clinical trials and the methods for testing new agents in an efficient way.

There are several key principles that the next era of Phase 1 trials has to tackle:

• Competence in assessing dosage by toxicity
• Effective integration of consistent expansion models
• Advancements in genomic and biological marker driven approaches.

Conducting Oncology Trials – Adaptive Designs

Oncology drug development involves roughly seven years of clinical assessment and often delivers an almost discouragingly low rate of success – as little as 7 percent of oncology therapies gain regulatory approval and are marketed. As investigational new drugs reach Phase 1 testing pharmaceutical companies and manufacturers are desperately seeking new ways to thoroughly evaluate potential therapies.

Traditional “fixed” trial designs use a probability-based strategy. Decisions are taken beforehand on dose, randomization, and sample size, which usually are not modified during the testing. Testing that follows an adaptive design, on the other hand, is more flexible. The as clinical trial’s course can be modified, often making it more efficient, comprehensive and informative.

Continual Reassessment Method

The predominant focus at Phase 1 is often on assessing the experimental drug's maximum tolerated dosage (MTD) and also the recommended dosage (RD) for future Phase 2 trials. The RD is often erroneous given the wide variations in the responses of patients so there is a longstanding dilemma, that is, researchers want to quickly increase the dose rate in order to give patients an “optimal” dose. However, a sudden rise in the dosage can lead to potentially fatal toxicity or even premature deaths that can be prevented with a prudent dose-escalation trial. In the conventional system, when a set number of patients do not demonstrate the dose-limiting toxicity (DLT) specified in the trial regimen, the dose level is increased.

The continuous reassessment method (CRM), proposed by O'Quigley et al., is based on Bayesian methodology and its aim is to minimize the number of patients undergoing ineffective lower doses and then to achieve an increasingly accurate figure of the MTD. The continuous reassessment method has proven to be better in some ways compared with conventional techniques. The CRM method provides a quantitative understanding of the probability of incidence of DLT. CRM also brings forth the probability of explaining the uncertainty of the dose to toxicity interaction prior to the actual study by using existing information from different sources.

Quantitative Imaging

The execution of oncology drug trials throughout the 21^st century is likely to be reflective of the increasing awareness that efficient cancer treatments may need to be individualized or used in combination.

Imaging techniques in combination with molecular assays are valuable tools to aid the decision as to “proceed” or “halt” development of a drug – in both preclinical and clinical phases.

Recent efforts to test a variety of molecular targeted drugs with unique effects across numerous tumor stages has demonstrated the shortcomings of anatomic imaging-based response standards. Trials incorporating molecular targeted drugs present opportunities for several crucial aspects of clinical design to establish and standardize innovative, practical imaging parameters.

The MTD may not be applicable in Phase 1 drug trials of molecular targeted drugs. To determine the minimum dose necessary for bioactive drug delivery at the specified site biomarkers are required. Quantitative imaging (QI) methods can then be used to illustrate the delivery of drugs to the specified site of the tumor and/or predisposing factors like physiological changes related to target modulation.

When recruiting for QI clinical studies, researchers can face patient apprehension. QI clinical trials are extremely time-consuming, and some procedures, such as FDG-PET, require several hours spent on-site while maintaining parameters like fasting. Researchers also found that QI trials that are closely aligned with trials for new modes of therapy seem to receive patients faster than mere imaging trials (other than screening). Patients are determined to gain access to new therapies, and QI may be recognized as an important component of the study. Patients have indeed raised concerns about the increased risks associated with QI elements in clinical studies. These worries can be resolved by providing clarification of what is to be expected and the protocols associated with the procedure.

Dose Expansion Trials

Molecularly targeted drug trials have allowed clinical researchers to significantly improve the therapeutic outcomes for particular patient demographics. These developments have intensified the need to test antitumor activity as fast as possible well into the drug development cycle, culminating in the advent of Phase 1 tests for larger populations of participants, intended to provide early clinical evidence of both efficacy and safety. Phase 1 research prototypes are gradually expanding past their previous emphasis on safety and are instead looking to find the most successful agents by introducing dose-expansion cohorts (DECs) before progressing to Phase 2 trials.

Such Phase 1 trials now often involve a dose-escalation procedure that establishes the MTD, preceded by a dose-expansion phase to specify the RD. DEC’s qualifying criteria for patients are often limited and focus on target specific molecular properties, types of diseases or sometimes both. DEC studies have varied objectives — to ensure that a safe dosage level has been identified, to gain tentative therapeutic benefits, and to identify specific demographics of patients that could potentially benefit from the clinical trial.

DECs enable researchers to limit the trial population to a specific subgroup of the patient population during Phase 1 trials. As a result, multiple Phase 2 trials are not needed, thus reducing the costs associated with multiple Phase 2 trials. It demonstrates a much-favored safety and efficiency across all the trials conducted with various dose levels.

The Validity of Phase 1 Trials

Oncology early phase trials, specifically the Phase 1 trials, have been typically recognized as “toxicity tests” and are considered to be of little clinical benefit apart from that of determining the adverse effects of the drugs that are being tested. The transition from three separate clinical trial stages into the implementation of target-specific therapies and immunotherapy has particularly influenced early phase trials and has contributed to the current scenario where response outcomes from early phase clinical trials are increasingly progressive.

Author Biography 

Cody J. Bollerman works with Synteract, a full-service clinical research organization offering a standalone service including clinical operations, biostatistics and data management.