Breast Cancer PARP PET Imaging AIP to Support FDA Approval & Commercialization

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Abstract: Poly (ADP-ribose) polymerase (PARP) inhibitor drugs (PARPi's) have emerged as important new therapeutic agents targeting a broadening class of gene mutations present in breast, ovarian, prostate and a host of other cancers. Identification of patients who might benefit from PARPi's has relied on assays for defects in homologous recombination (HRD), such as BRCA1/2 mutations, but these assays have been imperfect predictors of response to PARPi's. Drug binding to PARP1 present in tumor cells is a common and necessary factor for effective PARPi therapy. [18F]fluorthanatrace (FTT) is a PET-labeled analog of the PARPi rucaparib, and early clinical data in ovarian and breast cancer trials support [18F]FTT tumor uptake as an in-vivo measure of regional PARP1 drug binding, and indicate the potential of [18F]FTT PET as a PARPi predictive imaging biomarker. [18F]FTT could therefore provide benefits for patients with breast and other cancers by identifying those most likely to respond to PARPi therapy, while sparing those who will not respond from toxicity, unnecessary expense, and wasted time. To further the development, clinical translation, and commercialization of [18F]FTT, we propose an Academic Industrial Partnership (AIP) comprised of The University of Pennsylvania ((Penn), lead academic partner), MD Anderson Cancer Center(MDACC), and Washington University (WU) with Trevarx Biomedical, Inc (Trevarx). Trevarx, a radiopharmaceutical corporation with the exclusive license for [18F]FTT, is developing [18F]FTT as an imaging biomarker to guide PARPi treatment, with a first indication in breast cancer. Based on discussions with the FDA and advisors, [18F]FTT approval will require a Phase 3 study of the accuracy of [18F]FTT PET/CT for diagnosing PARP1 expressing cancer. The aims of this AIP proposal focus on critical components necessary for a Phase 3 trial for [18F]FTT FDA approval: (1) a Trevarx-held IND with standardized tracer production methodology and product specification; (2) validation of an immunohistochemistry (IHC) assay of PARP1 expression in formalin-fixed paraffin embedded (FFPE) tissue as a reference standard for [18F]FTT PET diagnostic accuracy; and (3) a Phase 2 multi-center trial to test and validate methods in a multi-center setting and provide preliminary data to design the pivotal Phase 3 trial. Completion of the these aims will enable a Phase 3 trial to support [18F]FTT FDA approval, commercial supply of [18F]FTT, and ongoing research by the academic partners to document the value of [18F]FTT PET/CT for guiding PARPi treatment, including prospective multi- center biomarker-focused studies.