In 2023, the American Society of Clinical Oncology (ASCO) and the Society for Neuro-Oncology (SNO) hosted a conference to address some of the important challenges in CNS drug development. One of the areas of focus for the meeting was innovative trial designs including master protocol trials such as basket trials. Basket trials evaluate a single investigational drug or drug combinations across different disease populations defined by a common characteristic, such as a genetic biomarker. The review published from the meeting points out that basket trials are particularly useful for neuro-oncology for several key reasons, summarized below.
Benefits of Basket Trials in Neuro-Oncology
Targeting Rare Tumors: CNS tumors are often rare and diverse, making it challenging to conduct individual trials for each type. Basket trials allow for the inclusion of multiple tumor types with a common genetic or molecular characteristic, facilitating the study of rare CNS tumors. One example is the ROAR trial. This trial tested dabrafenib and trametinib in patients with low-grade and high-grade gliomas, showing significant responses in these rare tumor types.
Efficiency in Drug Development: Another way basket trials may be useful in neuro-oncology is that they offer efficiency in drug development. By focusing on a common characteristic (e.g., a genetic mutation), basket trials can streamline the drug development process, making it more efficient and cost-effective. The ROAR trial led to accelerated regulatory approvals of drugs targeting specific mutations, benefiting patients with CNS tumors.
Access to Targeted Therapies: Basket trials can also offer broader access to targeted therapies for patients with CNS tumors that share molecular characteristics with other tumor types. One such basket trial is the VE-BASKET trial, which evaluated vemurafenib in non-melanoma tumors with a V600E mutation, including gliomas, demonstrating the drug’s efficacy across different tumor types.
Overcoming Logistical Challenges: Conducting individual trials for each rare CNS tumor type would require significant resources and time. Basket trials allow for the more efficient use of resources by combining tumor types into a single trial. The NAVIGATE and SCOUT trials assessed larotrectinib for NTRK fusion-positive CNS tumors, showing benefits for these tumors without the need for separate trials.1
Potential Imaging-Related Challenges in Basket Trials
While their potential usefulness is clear, there are challenges with basket trials that may make implementing them difficult. In particular, imaging in basket trials may present several challenges.
Tumor Heterogeneity: Tumors demonstrate substantial inter- and intra-tumor heterogeneity.2 Different tumor types, even with the same mutation, can exhibit significantly different biological and imaging characteristics, complicating the interpretation of imaging results.
Standardization of Imaging Protocols: Variability in imaging techniques (e.g., MRI, PET, CT) and in imaging protocols across different sites can lead to inconsistencies in data collection and analysis. Adherence to Imaging Charters and Image Acquisition protocols is particularly important in the context of basket trials.3
Response Criteria: The use of multiple response criteria in some basket trials (e.g. RECIST 1.1 and RANO 2.0) may present logistical challenges for readers if multiple imaging platforms are required, increasing training time and the time it takes to perform reads for each subject. Moreover, different types of CNS tumors can present different imaging characteristics. For example, high grade gliomas manifest with intratumor enhancement while low grade gliomas tend to be assessed by non-enhanced components; this can lead to different approaches when utilizing RANO 2.0 criteria.
Longitudinal Monitoring: Tracking changes over time in various tumor types can be challenging, as different cancers may respond differently to treatment, complicating temporal imaging assessments.
Radiologist Training: Radiologists may need additional training to recognize and interpret imaging findings in a wide variety of tumor types encountered in basket trials.
How MERIT Can Help
MERIT, an Imaging Core Lab (ICL), is a specialized type of Contract Research Organization that focuses on providing the data to support a study’s endpoint(s). We provide image analysis services including exam collection, quality checks, and independent, blinded reads, as well as data management services. Most importantly, we provide a pathway to regulatory approval as set forth in the 2018 FDA Guidance, “Clinical Trial Imaging Endpoint Process Standards: Guidance for Industry.” Phase II and III trials require an ICL for regulatory approval.4 ICLs can provide solutions for imaging challenges; MERIT accomplishes this by offering the following:
- EXCELSIOR™, an integrated, configurable, and flexible data and analysis platform that enables the use of multiple reading criteria in a basket trial to fit any protocol
- Subject matter experts to provide advice on reading criteria and endpoint selection from board-certified oncologists and expert radiologists serving as readers. MERIT’s access to a large pool of readers ensures reads are completed by radiologists that are experienced in the disease indication and response criteria for each study
- Experienced operational team that assists with imaging parameters and acquisition guidelines, including developing Imaging Charters, site manuals, reader training materials, data management, and reader monitoring
- Risk management in independent, blinded central review for data analysis and submission, including designing customized reading paradigms
- Quality assurance through rigorous reader training and oversight to reduce bias and variability across clinical trial sites
Conclusion
Basket trials are a powerful tool in neuro-oncology, enabling the efficient study of rare and diverse CNS tumors, providing access to targeted therapies, and overcoming logistical and biological challenges. They play a crucial role in accelerating the development of effective treatments for patients with CNS tumors.
About MERIT
Through innovative and proven technologies, alongside our intuitive, seamless workflows, MERIT’s experienced staff bring more than a decade of clinical endpoint expertise, ensuring the success and integrity of your clinical trials. MERIT supports clients in completing studies on time and on budget through:
- Clinical trial excellence
- Innovative single platform EXCELSIOR for all imaging activities and data collection
- Experienced and tenured oncology team
- Proven SOPs and workflows
- Established regulatory and QA
- Data Security and Privacy
References
1Rahman R, Polley MC, Alder L, Brastianos PK, Anders CK, Tawbi HA, Mehta M, Wen PY, Geyer S, de Groot J, Zadeh G, Piantadosi S, Galanis E, Khasraw M. Current drug development and trial designs in neuro-oncology: report from the first American Society of Clinical Oncology and Society for Neuro-Oncology Clinical Trials Conference. Lancet Oncol. 2023 Apr;24(4):e161-e171. doi: 10.1016/S1470-2045(23)00005-0. PMID: 36990614; PMCID: PMC10401610.
2García-Figueiras R, Baleato-González S, Padhani AR, Luna-Alcalá A, Vallejo-Casas JA, Sala E, Vilanova JC, Koh DM, Herranz-Carnero M, Vargas HA. How clinical imaging can assess cancer biology. Insights Imaging. 2019 Mar 4;10(1):28. doi: 10.1186/s13244-019-0703-0. PMID: 30830470; PMCID: PMC6399375.
3Ellingson BM, Brown MS, Boxerman JL, Gerstner ER, Kaufmann TJ, Cole PE, Bacha JA, Leung D, Barone A, Colman H, van den Bent MJ, Wen PY, Alfred Yung WK, Cloughesy TF, Goldin JG. Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials. Neuro Oncol. 2021 Feb 25;23(2):189-198. doi: 10.1093/neuonc/noaa253. PMID: 33130879; PMCID: PMC7906061.
4U.S. Food and Drug Administration. Clinical Trial Imaging Endpoint Process Standards Guidance for Industry. April 2018. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-imaging-endpoint-process-standards-guidance-industry