Deciphering the Acidic Tumor Environment: A Phase I/IIa Study of Pre-Operative Multiparametric MRI and pHLIP® ICG Intra-Operative Fluorescence Imaging of Primary Breast Cancer

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PROJECT SUMMARY/ABSTRACT Breast cancer (BC) is the most common cancer in women and the most common cause of female cancer deaths. While breast conserving surgery (lumpectomy) with neo/adjuvant therapy is the best desirable treatment option, about 25% of cases require secondary surgery when tumors are incompletely removed, with possible additional complications, patient anxiety, and conversion to mastectomy. Re-excision rates are especially high among patients with more aggressive tumors, which are characterized by acidic tumor microenvironment (TME). We propose to develop and implement a holistic approach for tumor acidity imaging with pre-operative multi- parametric MRI (mpMRI) and novel pHLIP® ICG near infrared fluorescent (NIRF) intra-operative imaging. pHLIP- ICG is an ICG, FDA-approved NIRF indocyanine green dye, conjugated to a pH-sensitive pH-Low Insertion Peptide (pHLIP) for targeting tumor cell surface acidity and for marking the invasive acidic tumor-stroma interface, thereby allowing pHLIP-ICG to target cancer lesions and to delineate positive tumor margins. Our clinical study consists of a prospective first-in-human phase I trial and a feasibility phase IIa trial. Aim 1 (phase I and IIa): To prospectively develop, implement, and optimize novel mpMRI sequences in consecutive BC patients undergoing lumpectomy for clinical non-contrast non-invasive assessment of the TME and tissue acidity including intravoxel incoherent motion diffusion-weighted imaging, diffusion tensor imaging, lactate MR spectroscopy, and chemical exchange saturation transfer imaging. Aim 2 (phase I): To evaluate the safety and tolerability of intravenous pHLIP-ICG administration in 4 dose levels in patients with primary BC undergoing lumpectomy, and to establish the “optimal” dose which will be used in the phase IIa trial. This optimal dose is defined as the lowest dose that is safe and that allows the best intra-operative visualization of BC with pHLIP- ICG NIRF imaging. Aim 3 (phase IIa): To establish the feasibility of pHLIP-ICG targeting and intra-operative imaging of primary BC and margin delineation at the selected optimal dose of pHLIP-ICG using histopathology as the reference standard. Aim 4 (phase IIa): To correlate TME acidity imaging (non-contrast non-invasive pre- operative mpMRI, and intra-operative and ex vivo pHLIP-ICG NIRF imaging) with standard histopathology and investigational immunohistochemistry for concordance and accuracy of BC visualization, margin status, and properties of the TME including different levels of acidity, lesion extent, and TME structure. The overarching long-term goal is to improve the standard of care: i) pre-operative non-invasive, non-contrast TME acidity imaging with mpMRI will allow the identification of more aggressive tumor phenotypes that require intensified treatment, improve planning of surgical and treatment strategies, and enable monitoring spatial-longitudinal of tumor biology with treatment; and ii) intra-operative pHLIP-ICG NIRF imaging will allow an improved up-front resection of primary breast cancer, which could allow a shift from more extensive surgeries to highly accurate tissue-sparing lumpectomies – therefore improving the quality of patients’ lives.