Walsh, Elaine M.

e12641 Background: Many promising agents or combinations regimens relevant to breast cancer lack sufficient clinical information for use in the neoadjuvant setting. To enable acceleration of drug development by reducing time and cost of clinical trial planning and conduct, the Phase I initiative PRE-ISPY Program was created. Methods: The PRE-ISPY Program is built within the I-SPY network, with the overall aim to streamline the regulatory pathway and the processes of trial design, contracting, activation, enrollment, execution, data gathering and analysis, as well as reporting of new therapeutic agents or combinations of relevance to breast cancer. Results: The PRE-ISPY trial is an open-label platform phase IB study designed to evaluate compelling single agent or combination regimens with the overall goal of moving promising drug regimens into I-SPY2 Trial and/or into other oncology-based trials in a timely manner. Graduation of a PRE-ISPY regimen to I-SPY2 is not mandatory. The primary objectives in each study Arm are to determine safety and to obtain preliminary efficacy data of the new regimen in patients with metastatic cancer, including a cohort of breast cancer patients. Each Arm may contain a Part 1 (dose finding) and a Part 2 (dose expansion). The new treatment can be tested also in patients with other solid malignancies than breast cancer, in which the treatment may be applicable, as specified in the design of the Arm. A breast cancer specific cohort is required in Part 2. Candidate treatment regimens are selected with advice from the I-SPY2 Agent Selection Working Group. The PRE-ISPY/Phase IB trial has multiple ongoing drug regimen Arms subsequently added as new protocol appendices through amendments to a Master protocol. There is no randomization; participants are enrolled, and treatment selected according to the relevance of therapy to their disease. Prospective companion biomarkers are evaluated. The current arms under study are PRE1: ALX-148 combined with trastuzumab deruxtecan; PRE2: tucatinib combined with zanidatamab; and PRE3: vidutolimod combined with cemiplimab. Selected agents or therapeutic combinations are tested through this protocol in the I-SPY Network Centers that participate in the PRE-ISPY Program. Toxicities are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Clinical responses are evaluated based on RECIST v1.1 criteria. Conclusions: Once safety is established, promising regimens can be rapidly transitioned to I-SPY 2.2 or other phase 2/3 trials. The first patient was enrolled on 2/1/2023. Clinical trial information: NCT05868226 .

TPS632 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for male breast cancer. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across nine (9) sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy for the current breast cancer or any other malignancy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity component in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for three weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) versus tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) versus anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is four (4) months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha=10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: estradiol and testosterone levels at baseline, end of window, and during neoadjuvant phase; preoperative endocrine prognostic index (PEPI) score at surgery; adverse events; and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened to enrollment at Dana-Farber in October 2023, and additional sites will open in 2024. Clinical trial information: NCT05501704 .