What is Project Optimus, and what problem is it trying to solve in oncology dosing?

The Food and Drug Administration (FDA) launched Project Optimus, an initiative to establish a dose-optimisation paradigm for cancer therapies. The goal is to collaborate with medicine developers, academia and patients to develop oncology therapies with dosing regimens that improve safety while maintaining efficacy.

Put simply, Project Optimus aims to ‘reform the dosing paradigm in oncology drug development.’¹

This blog explores the principles and recommendations of Project Optimus, including the role of pharmacokinetic (PK) and pharmacodynamic (PD) data, dose-response and exposure-response analyses, safety and tolerability assessments, and the use of randomised dose-comparison studies.

It also examines the FDA's recommendations across different stages of clinical development and reviews how global regulatory agencies, including the European Medicines Agency (EMA), are approaching dose optimisation for targeted therapies, monoclonal antibodies (mAbs), immune-modulating compounds and combination therapies for oncology.

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What does Project Optimus propose?

The FDA’s dosage optimisation recommendations emphasise a shift toward a data-driven, patient-centric approach to drug development. The overarching goal is to identify an optimised dosage that maximises the benefit–risk profile by providing the desired therapeutic effect while minimising toxicity, rather than simply finding the MTD.² The FDA also outlines that review through an expedited programme, i.e. breakthrough therapy designation, does not justify avoiding the need to conduct dosage optimisation before or at the same time as establishing a drug’s safety and efficacy. ² Taking advantage of early FDA engagement is recommended, as oncology development programmes can vary tremendously.

Core principles of the dosing strategy

PK and PD data: ²

• Include a PK sampling and analysis plan in every protocol to characterise the PK such as linearity, absorption, distribution and elimination.
• Initiate population PK and dose-response/exposure-response analyses early and update them as data becomes available.
• Evaluate the effects of food and potential drug interactions early in development to support the dosage selected for pivotal trials.

Intrinsic factors and subpopulations: ²

• Evaluate the impact of factors like genetic variation and organ impairment early; if alternative dosages are identified for specific subpopulations, incorporate them into pivotal trials when feasible.

Trial design for dose comparison: ²

• Compare multiple dosages in trials designed to assess anti-tumour activity, safety and tolerability.
• Use randomised, parallel dose-response trials to minimise bias and improve the comparability of patients.
• Consider adaptive designs to stop enrolment in inferior dosage arms based on interim assessments.
• Evaluate adding more patients to existing cohorts (backfilling) to gather more data before initiating randomised comparisons.

Safety and tolerability assessments: ²

• Compare dosages based on long-term tolerability metrics, including the proportion of patients requiring dose interruptions, reductions or discontinuations.
• Carefully assess persistent low-grade (Grade 1-2) symptomatic toxicities, as these can significantly impact a patient's ability to remain on treatment.
• Incorporate patient-reported outcomes (PROs) to systematically quantify symptomatic side effects and their impact on patient function.
• Pre-specify trial stopping rules for excessive toxicity in protocols.

Drug formulation:²

Plan for various dose strengths to facilitate the evaluation of multiple dosages; difficulty in manufacturing is not considered a sufficient reason to avoid comparing doses.

Subsequent indications:²

Tailor dosages for different disease settings or combinations, as different populations may require different doses based on tumour biology or concurrent therapies.

Dosing recommendations by development phase

1. Early development: Focus on characterising PK and identifying PD endpoints for both safety and activity. Sponsors should consider backfilling cohorts during initial dose escalation to gather more robust data early on and evaluate preliminary dose-response relationships.¹
2. Dosage optimisation phase: This phase should involve randomised trials evaluating multiple dosages in patients, targeting specific diseases. The goal is to further characterise dose- and exposure-response relationships to select the best dosage for registration.¹
3. Registrational trial: Using the selected optimised dosage, this trial focuses on developing a comprehensive assessment of the drug’s efficacy, safety and tolerability to support a marketing application.¹

Additionally, the FDA recommends using the totality of data at each step of development. Dosage selection should be based on an integrated assessment of all available information, including non-clinical data, PK, PD, safety, tolerability, dosage convenience, clinical activity, and established dose- and exposure-response relationships.¹

Global regulatory guidance for dose selection in oncology medicines

Although Project Optimus is a standalone initiative by the FDA, the EMA is also taking strides to ensure dose selection and dose optimisation in oncology therapies are developed in line with the evolution of MTAs, immunomodulating drugs and other non-cytotoxic agents.³

European Medicines Agency’s guidance

Non-cytotoxic compounds

Unlike traditional chemotherapy, non-cytotoxic compounds (e.g. signal transduction or cell cycle inhibitors) are typically administered continuously, and toxicity may not be the most appropriate endpoint for dose-finding trials.³

In cases where MTD is not adequate to establish the recommended dose, dose escalation can be based on PD and safety data in relevant animal models, and on human PK/PD data from initial and later dose cohorts, as well as using mechanism-based PK/PD modelling.³

Dose-finding for MTAs should extend beyond a purely safety-focused approach to identifying the optimal biologically active dose, defined as the dose at the start of the dose-response plateau, where higher doses provide no additional benefit.³

Because these therapies are often administered continuously for long periods, traditional DLT and MTD definitions must be broadened beyond Cycle 1 to capture late-occurring severe toxicities and persistent low-grade toxicities that impact long-term tolerability. Consequently, the RP2D should be determined through an integrated assessment of safety and activity across the entire treatment course to ensure the selected dose is tolerable for long-term use.³

mAbs and immune-modulators

mAbs:

In vitro non-clinical studies should be used to understand the main activity of mAbs and may include assays on target binding, potential "unwanted" targets, and both Fab- and Fc-associated functions.³ Continued evaluation of PK during clinical development involving different tumour types and disease stages is encouraged to characterise the often-seen non-dose-proportional PK behaviour of mAbs.³

Immune-modulating compounds/vaccines:

Non-clinical in vitro and in vivo proof-of-concept studies are necessary to justify the planned starting dose and schedule in phase 1 studies. On a case-by-case basis, the rationale for the starting dose may be supported by using the ‘Minimal Anticipated Biological Effect Level’ approach and by non-clinical and clinical data from related compounds.³

Early clinical trials aim to determine the safety and the dose and schedule that induce a desired immune response. Dose-finding studies are generally required to establish the RP2D. Monitoring the immune response, i.e. the induction of antigen-specific T cells or the presence of a humoral response, can determine the appropriate dose and schedule. Therefore, multiple monitoring assays may be necessary and should be explored.³

The design of clinical studies using clearly experimental therapies in patients with limited and measurable disease, not heavily pretreated with cytotoxic regimens, has to be justified. As for other agents, evidence of anti-tumour activity is essential prior to starting confirmatory studies.³

Combination therapy studies

Irrespective of the class of medicinal product and if there are no informative PD endpoints suitable for dose optimisation, dose finding relies on toxicity and tolerability.³

The dose-finding study design depends on the class of drug, including the need for prolonged treatment and DLT/safety observation time to identify dose-limiting but late adverse reactions of many non-cytotoxic agents.³

The optimal dose intensity of the individual compounds in the regimen is rarely identifiable in terms of both safety and efficacy. For combinations where co-enhancement of pharmacology activities and worsening of the safety profile of the combination compared with single partner are anticipated, particular attention should be paid to the need for a dose-finding combination study before conducting phase 2 studies.³

Comprehensive PK/PD assessment for potential interactions and characterisation of on- and off-target toxicities are particularly important in combination studies. Apart from identifying a regimen that is tolerable, sponsors should aim to identify the product(s) causing the observed adverse reactions in order to guide dose reductions in relation to observed toxicity. The toxicity profile of the drugs used as monotherapy provides some guidance, but class experience, mode of action, etc. should also be considered.³

Summary

Project Optimus aims to reform the traditional oncology dosing paradigm by encouraging the selection of doses that optimise efficacy, safety and long-term tolerability rather than simply identifying the maximum tolerated dose. The FDA's recommendations emphasise the importance of integrating PK, PD, dose-response and exposure-response data throughout development to support evidence-based dose selection.

The initiative advocates for the evaluation of multiple dose levels, comprehensive safety and tolerability assessments, the incorporation of patient-reported outcomes, and the consideration of intrinsic patient factors and specific subpopulations. It also outlines a structured approach to dose optimisation across early development, dedicated dose-optimisation studies and registrational trials.

Beyond the FDA, global regulatory agencies are increasingly recognising the need for alternative dose-finding strategies for modern oncology therapies. EMA guidance highlights the importance of identifying the optimal biologically active dose for non-cytotoxic agents, broadening toxicity assessments to capture long-term tolerability, and tailoring dose-finding approaches for monoclonal antibodies, immune-modulating therapies and combination regimens.

Together, these recommendations reflect a broader shift towards more robust and scientifically informed dose optimisation strategies designed to improve patient outcomes and support the development of safer, more effective oncology medicines.

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