Sandra J. Casak, MD, discussed future thinking around clinical trials in cholangiocarcinoma (CCA), a hot topic as there continues to be a need for effective new therapies for patients with CCA. A traditional drug development approach for oncology drugs is considered “phased” and consists of phase 1: safety, tolerability, and dose findings studies; phase 2: dose ranges, further safety, and preliminary activity studies; phase 3: large, multicenter risk/benefit assessments; and phase 4: postmarketing studies. This approach can be time consuming and requires multiple trials for a drug to be approved, demonstrating a need for a drug development process that expedites drug approvals.1,2 The distinct phases of drug development have become increasingly blurred, however, forgoing the standard approach and instead adopting a “seamless” oncology drug development paradigm that includes multiple expansion cohorts.1,2
Innovative clinical trial designs, including master protocols and adaptive trials, can provide a more flexible and effective way to conduct clinical trials. Patient-reported outcome assessments in clinical trials are crucial to assessing the benefit of any treatment and have become increasingly incorporated into trial design.3 In addition, decentralization of clinical trials can decrease patient burden and increase accrual and retention of a diverse population.3 Real-world data and evidence are also making their way into clinical trials where artificial intelligence will become a prominent aspect in medicine to revolutionize the clinical trial landscape.3 These advances in clinical trial design are only possible with partnerships across a variety of stakeholders, including pharmaceutical manufacturers, academia, federal agencies, and patient advocacy groups.3
Future thinking for clinical trials should be informed by past experiences to address ongoing issues. Diversity and representation in clinical trials has been an ongoing problem, and CCA trials should be designed to be multiregional to include a diverse variety of populations.3 Although clinical trials in CCA have included many regions, such as North America, Europe, Asia, and South America, the populations included did not reflect the diversity of these regions and included 49% White patients, 39% Asian patients, 3% Black patients, and only 5% Hispanic/Latino patients.3 In addition, the median age of CCA diagnosis in the United States is 70 to 72 years; however, the median age of trial participants for CCA is 59.1 years, with only 39% being older than the age of 65.3 In 2022, the FDA enacted the Food and Drug Omnibus Reform Act, which requires increased enrollment from historically underrepresented populations.3
Another important consideration for clinical trial design is the inclusion of patients with less advanced disease.3 Currently, clinical trials are mostly reserved for patients with late-stage disease who have been treated with ≥1 prior lines of therapy.
Dose optimization is another area of need in clinical trial design.3 Future clinical trials should be designed to conduct proper dose optimization and incorporate those strategies into drug development. Traditional chemotherapy toxicity and efficacy curves are parallel, and toxicities tend to increase with increasing doses; however, that paradigm does not apply to targeted drugs.3 In 2 of 3 approved FGFR inhibitors, more than half of patients required dose reductions, typically due to tolerability of the studied doses, which initiated postmarketing dose optimization studies to evaluate lower doses.3 Dose optimization should not be considered after clinical studies are completed and can reduce toxicities and increase adherence to treatment when studied earlier. Project Optimus aims to improve dose optimization in clinical trials, and in 2023 the FDA published a guidance for industry document that includes recommendations for each stage of drug development.4
Another important consideration for clinical trial design is the inclusion of patients with less advanced disease.3 Currently, clinical trials are mostly reserved for patients with late-stage disease who have been treated with ≥1 prior lines of therapy. However, there may be important advantages to clinical trials including patients with earlier disease, such as earlier access to new therapies, fewer disease-related factors precluding patient participation, improved safety assessments and potential to avoid disease-related factors or sequelae from prior treatment, and the potential for comparison to the established standard of care and improvement of outcomes in the frontline setting.3 Project FrontRunner aims to facilitate engagement with drug sponsors during drug development to implement strategies to support approvals in early clinical settings.5
Finally, pragmatic trials may be applicable to combination therapies or drugs with extensive familiarity. Lung-MAP is an umbrella study that tests multiple treatments simultaneously under 1 protocol based on genomic profiling, and patients are matched to appropriate studies based on genomic testing results.6 Pragmatic trial design can speed up the clinical trial process, but data collection may be limited, safety analysis is only limited to grade ≥3 events, overall survival is studied as a single efficacy end point, and patients are treated and followed as in real-world practice.3
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