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The impact of FDA’s Project Optimus and Project FrontRunner

Posted on the 12th March 2024

Cancer Research

FDA’s Oncology Center of Excellence has initiated numerous programs and projects to advance the development of medical products for patients with cancer.

G&L Healthcare Advisors’ unrivaled subject matter expertise and decades of experience enable us to guide sponsors through this bewildering array of initiatives across all phases of development and to aid them in improving the efficacy and safety profiles of their products.

Below, we examine the goals, benefits, and challenges of two of these initiatives: Project Optimus and Project FrontRunner.

Project Optimus

Project Optimus1 seeks to reform the dose optimization and dose selection paradigm in oncology drug development to maximize not only the efficacy of a drug but the safety and tolerability as well. Historically, cytotoxic oncology drugs were developed in dose-escalation trials with determination of a Maximum Tolerable Dose (MTD). Subsequent investigations use doses near the MTD to provide optimal efficacy of the chemotherapy in specific tumor types. The rationale was that the drug would be taken up preferentially by the highly metabolizing tumor cells over the normal metabolizing healthy cells.

This paradigm has led to great strides in the development of novel targeted therapies with various selective mechanisms of action. However, the development paradigm using MTD can lead to initiation of registration trials with inadequately characterized doses and schedules for molecularly targeted therapies. Poorly characterized dose and schedule may result in selection of a dose for registration trials that provides more toxicity than necessary, resulting in severe adverse events that can limit a full course of treatment or produce long term toxicities. Many patients may require dose reductions, stop treatment altogether, or become ineligible to receive subsequent therapy because of toxicities.

To foster selection of doses that maximize not only the efficacy of a drug but the safety and tolerability as well, FDA has provided a draft guidance2 on dose optimization of drugs and biologics being developed for oncology. Sponsors are encouraged to leverage pharmacologic, toxicologic and pharmacokinetic data from nonclinical studies in dose selection as early as possible in the development program as a basis for clinical investigation. The use of nonclinical data is not new for the establishment of a starting dose.3 However, these data can also be useful for predicting efficacy to provide a starting point for dose optimization and the investigation of dose- and exposure-response relationships.

Typically, first-in-human studies in oncology settings4 are divided into a dose escalation phase using a small number of patients in each of the ascending dose cohorts followed by an expansion phase of 2 or more doses, which should also include randomized evaluations. Although it is typical in first-in-human oncology studies to use an “all-comers” approach in the dose escalation phase and then explore specific tumor types in the expansion cohorts, the overall patient numbers are often too small to support a recommended Phase 2 dose. An optimized dose paradigm includes evaluation of nonclinical data in conjunction with a clinical safety evaluation of dose by adverse events (number of events, grade, and frequency), discontinuations, dose modifications/dose interruptions in conjunction with clinical efficacy, and durability as a composite for recommended Phase 2 dose determination for a particular indication. Use of translational biomarkers and exposure-response analyses can also be valuable tools in understanding peak activity of the drug. This optimization of the recommended Phase 2 dose may need to be evaluated for each indication, depending on differences in the clinical settings.

The emphasis of Project Optimus is on encouraging sponsors seek doses that best balance efficacy and toxicity prior to conducting the registration trial and marketing. This strategy may facilitate FDA approval5 and can avoid costly delays due to a clinical hold on a registration study or problems resulting from a requirement for postmarketing comparisons of a labeled dose with a lower dose. The expertise, hard work, and flexibility of G&L staff can help guide sponsors through these challenges.

Project FrontRunner

Currently, drug development in oncology is generally initiated in patients who have received numerous prior lines of therapies or who have exhausted available treatment options. Project FrontRunner6 aims to shift the current oncology drug development paradigm from this focus on the relapsed and refractory clinical setting to developing therapies earlier in the clinical course, in order to provide patients with earlier access to safe and effective therapies during the initial course of their disease. Initiating the clinical investigation of new therapies in an earlier treatment setting would make better options available to patients at a point when the treatment has the potential to alter the course of the disease most effectively, with the greatest impact on the overall quality of life.

Testing new drugs in relapsed and refractory patients with advanced disease progression involves confounding effects of disease-related complications and sequelae of prior treatment. It is well known that testing in later lines of therapy involves lower response rates and more challenging overall efficacy and safety profiles. Evaluation of novel oncology agents in earlier lines of therapy would avoid these pitfalls.

Randomized clinical trials represent the gold standard for obtaining the data needed to facilitate a benefit-risk assessment at the time of approval. Another advantage of the FrontRunner approach is that randomized controlled trials are less challenging to conduct early in the course of advanced/metastatic disease. Larger patient numbers are available in the earlier setting, leading to faster recruitment. Also, more clinical data would be available to enable comparison of the efficacy and safety of the novel drug with an established standard of care.

In earlier treatment settings, new agents are often investigated as add-ons to standard therapy rather than being tested as monotherapy. Most patients are more willing to participate in an add-on trial of a new drug plus conventional therapy. As with Project Optimus, the recommended Phase 2 dose for the novel and approved agent combination should be optimized for efficacy and long-term tolerability, exposure-response relationships, and alignment with the nonclinical data.

The Project FrontRunner model may not be appropriate for every clinical setting or investigational drug. G&L Healthcare Advisors can help identify clinical settings where this approach would be feasible and appropriate.


Integration of the goals of Project Optimus and Project FrontRunner in clinical development plans for novel oncology agents will not only help sponsors in their interactions with FDA but will align the development of new oncology drugs with the patients’ best interests. The depth and breadth of G&L Healthcare Advisors’ expertise and experience can help sponsors navigate through the process of implementing these approaches.


1. U.S. Department of Health and Human Services Food and Drug Administration.

Project Optimus: Reforming the dose optimization and dose selection paradigm in oncology. Available from

2. U.S. Department of Health and Human Services Food and Drug Administration. Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases. Guidance for Industry. January 2023. Available from

3. U.S. Department of Health and Human Services Food and Drug Administration. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Guidance for Industry. July 2005. Available from

4. U.S. Department of Health and Human Services Food and Drug Administration. Expansion cohorts: Use in first-in-human clinical trials to expedite development of oncology drugs and biologics. Guidance for Industry. March 2022. Available from

5. Hansen AR, Cook N, Amir E, Siu LL, Abdul Razak AR. Determinants of the recommended phase 2 dose of molecular targeted agents. Cancer. 2017 Apr 15;123(8):1409-1415. doi: 10.1002/cncr.30579.

6. U.S. Department of Health and Human Services Food and Drug Administration.

Project FrontRunner: Advancing development of new oncology therapies to the early clinical setting. Available from

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