CLINICAL DEVELOPMENT IN ONCOLOGY “We are looking to get drugs to patients as


quickly as possible. While this is a noble gesture, it has some challenges in terms of what we are able to show is an effective and safe dose,” said Dr R Donald Harvey, professor at Emory University School of Medicine. “Efficacy is the bare minimum,” adds Namouni, who drives the argument that Project Optimus is a timely initiative with the potential to fine-tune drug development. Increased emphasis on optimal doses will allow patients to reap maximum benefits from treatment as they do not have to discontinue a given treatment due to toxicities. In addition, this is important because cancer can reemerge in the absence of treatment and lead to mortality, he explains. Therefore, Project Optimus is a bid for


balance: maintaining treatment efficacy at a therapeutic dose that does not generate toxicities that could otherwise be avoided with a different dose. What the FDA is asking pharma to do is implement cohorts and subsequent analyses, and fundamentally more observations of doses that are different from each other, experts agree.


Project Optimus: apply with care In the existing model, a handful of patients are evaluated at a dose that is adjusted according to response data, the adverse event rate, and clinical pharmacology. Given that a therapeutic’s tolerable side effects are different at initiation versus over a longer period of time, what the FDA is asking pharma to do is evaluate multiple, diverse doses that increase the knowledge surrounding a therapy, thereby maximising its potential benefits for patients. The reform in the dose optimisation model is needed because many drugs—particularly the newer, orally administered drugs—have a relationship between side effects and efficacy that is not linear, explains Harvey. A larger dose may correlate with an increasing side effect profile early on in the development lifecycle. But at some point, efficacy plateaus despite dose escalation, while side effects continue to increase in frequency and severity. This is the trajectory for many cancer drugs because the field actively follows a model of drug development where dose escalation is


10 | Clinical Trials in Oncology


“A key operational aspect of the Project is understanding the molecule more at the outset of human trials”


continued until problematic side effects materialise, at which point escalation is ceased. The key is to apply Project Optimus to the


right projects, as it could potentially be a hindrance when developing drugs with other modes of administration, Harvey explains. The biggest culprits for subpar doses are oral formulations and orally dosed medications such as capsules and tablets. Subsequently, these oral medications provide the biggest opportunity for Project Optimus to create an impact. “A key operational aspect of the Project is


understanding the molecule more at the outset of human trials,” explains Harvey. At early clinical stages, the drug profile of an intravenous therapy will be more extensively characterised than the profile of an oral drug because there is more available knowledge about the former. Oral formulations have more variability at the


outset, and subsequently more knowledge gaps regarding drug absorption and drug interactions, he adds. “If a new PARP inhibitor were to be


developed today, there would be a lot more known about it, and there would probably be a much more predictable dose. However, in terms of risk, if you have a brand-new antibody that is a first-in-class target, we’re going to know a lot more about that than we will a first-in-class oral agent,” Harvey says. Furthermore, Harvey believes the project will


be more applicable to drugs with mechanisms of action that have more data and proven history, as opposed to drugs with novel mechanisms that are first-in-class or


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