Page 14 - TD-2-2

Tumor Discovery Practice and consideration of master protocol design

a broad range of tumor types, in which sample size within and evaluation standards. In contrast to the high-quality
sub-studies is often small but yield quick results, given evidence from Phases I, II, and III trials in oncology drug
sufficient accrual . For example, BRAF V600 is a basket evaluation, most oncology devices classified as medium-
[5]
trial evaluating vemurafenib, the selective BRAF V600 risk (Class II) are approved via the premarket notification
inhibitor, in patients with eight nonmelanoma cancers . (510[k]) pathway to predicate devices and require only
[3]
This study recruited only 122 adults but led the FDA to preclinical supporting data. As a result, we have often
approve vemurafenib for treating BRAFV600-mutant assumed the effectiveness of a novel device based on
Erdheim-Chester disease. In addition, an umbrella trial technical and physical parameters without evidence from
in cancer can evaluate multiple targeted drugs with clinical trials. This premarket notification pathway causes
corresponding biomarkers for patients in single cancer, oncology device manufacturers’ unwillingness to sponsor
of which biomarker-negative patients are usually enrolled clinical studies of new oncology devices . Consequently,
[12]
into a “non-match” sub-study, thus evaluating the drug’s the master protocol trials of oncology devices are usually
purported mechanism of action more thoroughly. For after marketing approval and funded by academia. In
example, lung-MAP is an umbrella trial evaluating four addition, whereas oncology drugs primarily utilize
targeted agents with their corresponding molecular biomarkers as targets in master protocols, oncology devices,
markers in squamous cell lung cancer. In this trial, patients especially RODs, use tumor sites as therapeutic targets to
with no targeted biomarkers of interest are assigned to some extent. For instance, UMBRELLA-II trial evaluates
the “nonmatch” sub-study, allowing a more thorough the feasibility of various in-house developed techniques or
evaluation of the mechanism of drugs and more screened software on the MR-Linac, in which various tumor sites are
patients to participate . Finally, for a platform trial, considered as therapeutic targets . Furthermore, master
[9]
[13]
it can be more likely a specific form of a basket or an protocol trials in oncology devices refer to single cancer
umbrella trial mentioned above with perpetual features type-agnostic protocols encompassing multiple cancer
and adaptation [17-19] . For instance, I-SPY 2 is a platform type-specific sub-studies, of which the most common trial
trial evaluating multiple neoadjuvant therapies for high- design types are basket trials. For example, stereotactic
risk, locally advanced breast cancer with a trial network MR-guided adaptive radiation therapy (SMART) is a basket
and informatics infrastructure, including adaptations trial evaluating the feasibility and efficacy of stereotactic
of Bayesian decision rules and response-adaptive MR-guided adaptive radiation therapy in patients with
randomization for a more flexible design . Therefore, the 13 different types of cancer .
[8]
[31]
principles of master protocols closely match the mechanism
of oncology drugs and will be further developed and 4.2. In vitro diagnostic assays
applied to oncology drugs. Notably, in vitro diagnostic assays are classified as medical
4. Master protocol trials in oncology devices. Next generation sequencing (NGS) assays have
been widely adopted in clinical oncology by utilizing the
devices profiled genetic mutation information to select patients
In evaluating oncology devices, the pertinent clinical and guide the choice of target therapy. The NGS assays
question is which indications the new technology is better, are essential in the master protocol trial of oncology
to what extent, or whether it reduces toxicity . To address drugs. For example, in NCI-MATCH mentioned above,
[30]
these questions, some researchers use master protocol a single NGS assay is used to screen for the actionable
trials in oncology devices, which can test several clinical mutations in about 6000 patients who have relapsed or
indications in a standardized fashion, allowing for more refractory solid tumors and lymphomas after standard
rapid and direct comparisons of different indications systemic treatment, and assigned matched treatment .
[22]
and technologies. Here, we list the critical information of As conducting prospective clinical trials is necessary to
several representative master protocol trials in oncology acquire FDA approval for a biomarker-targeting oncology
devices (including hardware and software) in Table 2, drug, the development, and validation of NGS diagnostics
showing the considerations and clinical practices. assays that accurately and reliably report genetic mutation
status from patient tumor biopsies to determine study
4.1. RODs eligibility are instrumental to the success of such clinical
As is shown in Table 2, there are fewer master protocol studies. NGS assays used in clinical trials for guiding
trials in oncology devices reported than in oncology therapy decisions were considered investigational devices
drugs, mainly focusing on RODs. This situation is large and had to meet regulatory compliance for investigational
because drugs and devices have different FDA approval device exemption, such as the code of federal regulations
pathways, driving differences in clinical implementation title 21 part 812 for investigational device exemption .
[32]

Volume 2 Issue 2 (2023) 8 https://doi.org/10.36922/td.342