Table 1.

Redefining clinical trial paradigms and standard of care

Subject matter	Solution	Challenge
The definition of “personalized” treatment is inconsistent with canonical trial/practice paradigms, where patients are grouped together based on a biologic commonality.	A patient-centered, N-of-one approach is needed to optimize therapy.	Current treatment paradigms, including precision oncology trials, are drug centered rather than patient centered.
Mono-therapy is unlikely to cure patients with advanced/complex malignancies.	Combination therapies needed	Matched customized combinations for N-of-one tumors require evaluation of the strategy of personalization or an algorithm for matching, rather than the drug regimens themselves
The inimitability of tumors means that each cancer is akin to a malignant snowflake—both unique and complex in its genomic portrait.	Unique/complex tumors require individualized combination regimens	With 300 drugs, there are about 4.5 million three-drug regimens.
Dosing of combinations of anti-cancer drugs has traditionally required a phase I study.	Outside of oncology, patients regularly receive de novo combinations of drugs based on understanding impact on metabolic enzymes etc. The average oncology patient is already on eight medications, which have not been assessed together in a phase I study, but are given safely together. Dosing algorithms for anti-cancer drug combinations can be similarly derived from a variety of sources including the literature[57–60]	The pathway to approval and payor acceptance of drug combinations is unclear
If tumors are defined by their molecular makeup, advanced molecular tests should be considered a standard diagnostic tool for patients with cancer.	Universal genomic testing of cancers	Points and counterpoints in Table 2