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National Cancer Institute (NCI)

The goal of this funding opportunity announcement (FOA) is to improve the treatment of adult glioblastoma (GBM) by developing novel effective agents that can cross the blood brain barrier (BBB) and testing them in the clinic. Successful early stage trials of these new drugs would transition seamlessly to later stage trials using well-established NCI clinical trial mechanisms.

To implement this concept, a highly collaborative GBM Therapeutics Network (GTN) of cross-cutting teams will be established, each team capable of driving therapeutic agent(s) from pre-clinical development, through IND studies, into pilot clinical studies in humans. Appropriate candidates include: (1) novel agents or (2) agents or combinations approved for other indications and repurposed for treatment of GBM following appropriate preclinical studies. As developing drugs from the discovery phase is a long, expensive process that often encounters obstacles and failures, this FOA will focus on a cooperative effort in drug development, rather than on discovery. A unique aspect of the GTN will be the ability of members to leverage models and methodologies for cross-validation of promising agents across the network.

This Notice is being provided to allow potential applicants time to develop responsive projects and meaningful collaborations.

The FOA is expected to be published in September 2020 with an expected application due date in November 2020.

The FOAs will use the U19 activity code (Clinical Trial Required).

Details of the planned FOA is provided below.

Each team in the GTN will propose, using the U19 mechanism, a minimum of two scientific projects focused on agent(s) that have completed or are solidly in lead optimization status and are new to the treatment of GBM. If an agent has shown promise in preclinical studies but is still at the lead identification stage, the investigators will have to state how lead optimization will be accomplished within one year. Projects focusing on small molecules are preferred; biologic agents that target either the tumor or the immunosuppressive microenvironment and that meet the criteria for this concept may be proposed. Successful development of agents for GBM will depend on the use of animal models that closely mimic human adult GBM including assessment of passage through the BBB and ideally allow for repeated assessment of tumors over the course of disease treatment. Although components of each multi-disciplinary team will vary with the development stage of the proposed agent(s), it is anticipated that successful U19 teams will include outstanding expertise and experience in medicinal chemistry, pre-IND in vivo modeling, drug development (drug formulation, scale-up, ADMET, PK/PD assays and imaging), and clinical trials development and execution; it is imperative that each team include all the necessary expertise to advance the agent(s) to the clinic. Applicants to this FOA may include expertise from contract research laboratories or through public-private partnerships. Availability of primary human GBM samples and PDX models will also be important for efficacy testing in vitro and in vivo and, possibly, development of predictive biomarkers to guide early-stage clinical studies. One or more cores that support the scientific projects are required; projects and cores within each team should demonstrate synergy that could not be accomplished without extensive intra-U19 collaborations among components. As a cooperative agreement, a high level of programmatic guidance on trans-U19 coordination is expected.

Studies that focus solely on the biology of GBM and its tumor microenvironment as well as projects proposing extensive model development will not be responsive to this RFA.

It is expected that each U19 team will be composed of investigators from at least two institutions and may be led by multiple PD/PIs to accelerate the development of the candidate agent(s) proposed. Published or preliminary data demonstrating success in discovery of one or more lead candidates is necessary for FOA responsiveness. Specifically, data demonstrating the following for new or repurposed agents are required: validation of the proposed target(s) for GBM; process of lead selection, including structure-activity relationship data if the agent is a small molecule; potent target activity (IC50 in primary assay); selectivity for tumor versus normal cells, and selectivity for the proposed target versus analogous targets; chemical solubility; and in vivo efficacy in at least one model of GBM.

The GTN will require one Network Coordination Center to provide network harmonization on scientific and clinical activities. U19 teams may propose the Network Coordination Center as one component of the U19 application. Applicants who wish to apply for this role should provide a detailed work scope including coordination of biospecimen collection and transport, model sharing, development of standard operating procedures for the functioning of the network, and data management. Additional funds of up to $500K total costs per year will be allowed for the Network Coordination Center component. Only one such component will be chosen by the NCI for the GTN and will be guided by peer review.

U19 teams will cooperate so that reagents, assay protocols, animal models, patient samples, technologies, and development of clinical protocols are shared. As some teams will be further along in the process than others, when any one of the teams is ready to test their agent(s) in a pilot clinical trial, all other U19 sites are encouraged to participate as secondary sites as guided by NCI and GTN governance. A Steering Committee will be assembled to provide oversight of the transition of agents from pre-clinic to clinic.

For more details and to view the BSA presentation of the GTN, see: https://videocast.nih.gov/summary.asp?live=37597

To view the GTN slide set see: https://deainfo.nci.nih.gov/advisory/bsa/0520/Forry.pdf

Applications are not being solicited at this time.

Please direct all inquiries to:

Suzanne Forry, Ph.D.

National Cancer Institute (NCI)

240-276-5922

[email protected]