Phase II Study of Abemaciclib in Combination with Letrozole in Advanced, Recurrent or Metastatic Endometrioid Endometrial Cancer

1.1 Primary Objective 1. To determine the objective response rate of patients with advanced, persistent, or recurrent endometrioid endometrial cancer. 1.2 Secondary Objectives 1. To estimate the time to disease progression. 2. To describe the toxicities in patients receiving combination therapy with letrozole and abemaciclib with advanced/metastatic endometrial cancer. 1.3 Translational Research Objectives 1. Perform multiplexed protein expression analysis at a single cell level using imaging mass cytometry (IMC), exploring the relationship to response, and assessing for longitudinal changes upon progression/relapse. a. Cyclin D and E Pathway: Protein expression of CCND1, CDK4, CDK6, RB1, phospho-RB1, CDKN2A, CCNE1, CCNE2, CDK2, CCND3 b. Immune cell infiltration and activity: CD45, CD3, CD8, CD4, FoxP3, PD-1, Tim-3, CTLA-4, CD25, Ki67 c. Sex hormone/insulin/IGF pathway: Protein expression of ER (ESR1), PR, IR, IGF1R, and phospho-IGF1R/IR 2. Determine the frequency of Cyclin D1 3’UTR mutations and association with response. 3. Compare the pre- and post-treatment circulating estradiol and insulin levels, and association with response. 11 2.0. Background and Rationale The identification of novel targets in malignant tumors has led to the development of inhibitors for the treatment of a wide range of cancers. The challenges of developing rational targets for therapeutic intervention in specific solid tumors remain an area of intense research. Hormonally driven malignancies such as breast and prostate cancers are known to have actionable therapeutic targets. The current study will evaluate the efficacy of targeting hormonal regulation using dual estrogen-pathway specific treatments in women with recurrent or metastatic endometrial cancer. 2.1. Endometrial Cancer Endometrial cancer (EC) is the most common gynecologic malignancy with an estimated 61,880 cases in 2019 in the United States (Siegel, 2018). Projected trends anticipate as many as 122,000 new cases of EC by 2030 (Rahib 2013). Endometrial cancers are categorized as type I (low grade, typically endometroid) and type II (high grade, typically serous or clear cell). Low grade, endometrioid cancers typically arise in the setting of hyperestrogenism. The standard treatment for primary endometrial cancer consists of surgical resection and, in selected patients, radiation and/or chemotherapy. Recurrence is most common in women with advanced-stage disease or those with high risk features (high grade, lymph vascular space invasion, and deeply invasive disease). Women with recurrent disease other than isolated pelvic recurrence are primarily treated with systemic therapy.