Early-Stage Clinical Trials Underestimate Small Molecule, Targeted Anticancer Drug Toxicity

Dose-determining phase I clinical trials may not correctly determine the appropriate doses of small molecule oncology drugs to administer in larger, later stage trials.

Dose-determining phase I clinical trials may not correctly determine the appropriate doses of small molecule oncology drugs to administer in larger, later stage trials according to a new study published in Clinical Cancer Research.

Phase I, dose-elevating clinical trials in a small number of patients are the standard way to determine the appropriate doses to test in later stage clinical trials. These small trials analyze pharmacokinetics, pharmacodynamics, and toxicity to determine the drug doses and schedules that are most likely to balance safety and efficacy.

The current study, conducted by researchers at The Institute of Cancer Research  and the Royal Marsden Hospital NHS Foundation Trust in the United Kingdom, suggests that phase 1 dose-ranging studies do not correctly reveal the severity of side effects of these cancer agents. The result is high incidence of varying drug toxicity experienced by patients taking part in phase III oncology clinical trials testing targeted small molecule agents.

Udai Banerji MD, who designs and runs phase I clinical trials of personalized cancer therapies in development at the Institute of Cancer Research and his colleagues, concluded that the current methods used to make recommendations for phase III drug doses need to be improved.

Dr. Banerji and his colleagues reviewed previously published data on 34 molecularly targeted cancer therapies that were approved by the US Food and Drug Administration between 2002 and 2015. Twenty-eight drugs were small molecules and 6 were targeted antibodies. The researchers compiled clinical data from a total of 130 publications and abstracts on these molecules, comparing side effect data from phase I and phase III trials to understand how the initial safety results in a small patient cohort translated to a larger patient population that received the therapy for a longer time period.

The analysis showed that in phase III clinical trials, a significantly greater percentage of grade 3 or 4 adverse events were reported with small molecules compared to antibodies (40% compared to 27%, respectively; P = .038). Forty-five percent of patients treated with a small molecule agent needed a dose modification in a phase III clinical trial. Sixty-four percent of patients treated with a combination therapy in a phase III trial had high-grade toxicity compared to 37% of those treated with a single agent (P = .001).

Partly reassuringly, stated the authors, is that despite the increase in toxicity in late-stage trials, a relatively small percentage of patients (9%) discontinued a drug due to drug-related toxicity. In most cases, a dose interruption or dose reduction was sufficient to mange drug-related side effects.

Potential reasons for the increase in toxicity seen in phase III is the longer exposure to the experimental agent.

“While some drugs truly have a narrow therapeutic index and are destined to have toxicity, exploring intermittent schedules and determining pharmacodynamically active dose ranges can result in drug dose and schedules that are tolerable in larger populations of cancer patients. Better optimization of dose and schedules leading to less toxicity will be beneficial patients and healthcare providers alike,” concluded the study authors.