Abstract OT2-01-02: First in human phase 1 dose escalation and expansion study of the safety and pharmacokinetics of the oral CDK7 inhibitor XL102 as a single-agent and in combination therapy in patients with inoperable locally advanced or metastatic solid tumors, including breast cancer
Authors: Patnaik Amita , Barve Minal , Bhave Manali , Subbiah Vivek , Atwal Sumandeep , Sharma Keerti , Scheffold Christian , Wetmore Cynthia , Shapiro Geoffrey 
Published: March 2022

Abstract
Background: XL102 is an orally bioavailable, selective, and covalent small-molecule inhibitor of cyclin-dependent kinase 7 (CDK7). CDK7 is a serine/threonine kinase which controls cell cycle progression via the phosphorylation of CDKs (1, 2, 4 & 6) and regulates transcription through phosphorylation of RNA polymerase II. CDK7 overexpression has been reported in multiple tumor types including hormone receptor positive (HR+) breast cancer (BC) and triple negative breast cancer (TNBC). XL102 induced cell death in a number of cancer cell lines and caused tumor regression in murine xenograft models of multiple tumor types including HR+ BC and TNBC. Here, we present the study design of an ongoing phase 1 trial in solid tumors which includes cohorts with advanced HR+ BC, TNBC, epithelial ovarian cancer (EOC), and metastatic castration-resistant prostate cancer (mCRPC). Trial Design and Statistical Methods: This phase 1, open-label trial will assess the safety, tolerability, pharmacokinetics, anti-tumor activity and effect on biomarkers of XL102 administered orally alone and in combination regimens in selected tumor types (NCT04726332). The study consists of dose-escalation stages and disease-specific cohort expansion stages. In the dose-escalation stages (modified interval 3+3 design), a maximum tolerated (MTD) and/or recommended XL102 dose (RD) for use alone and in combination therapy with standard dose fulvestrant (HR+BC) or abiraterone/prednisone (mCRPC) will be established in independent strata. Upon reaching the MTD/RD, the expansion stage will enroll according to Simon’s Two-Stage Minimax design, assuming a power of 80% and one-sided α of 15%, for single agent XL102 (HR+BC, TNBC, EOC, and mCRPC) and XL102 in combination therapy (HR+BC and mCRPC). Eligibility criteria: All patients must have adequate organ function and be able to take oral medications. Patients with CNS disease are eligible if treated and stable, provided they meet the other inclusion and exclusion criteria. Patients enrolled in expansion cohorts must have measurable disease. Patients in HR+ BC expansion cohorts must have received ≥ 1 prior endocrine anticancer therapy and 1 prior CDK4/6 inhibitor therapy either sequentially or concurrently and may have received ≤ 2 additional prior lines of systemic anticancer therapy for locally advanced or metastatic disease. Patients in TNBC and EOC expansion cohorts must have received ≥ 1 line but &lt; 3 lines of prior systemic anticancer therapy for locally advanced or metastatic disease or platinum-resistant ovarian cancer (eg, cytotoxic therapy, targeted therapy, immunotherapy), respectively. Patients in EOC expansion cohort may include primary peritoneal cancer and fallopian tube cancer who have platinum-resistant disease following treatment with a platinum-containing chemotherapy. Patients with ovarian borderline epithelial tumors and platinum-refractory disease are ineligible. Study objectives: The primary objective of the expansion stage is the objective response rate of XL102 alone and in combination therapy as assessed by the investigator per RECIST 1.1. The secondary objectives are to evaluate safety, tolerability, and pharmacokinetics. Exploratory objectives include duration of response, progression-free survival, overall survival, and correlation of tumor and blood biomarkers with response. Accrual: The study began enrolling patients in February 2021 and is ongoing. Total enrollment estimated to be up to 298 subjects.
Citation Format: Amita Patnaik, Minal Barve, Manali Bhave, Vivek Subbiah, Sumandeep Atwal, Keerti Sharma, Christian Scheffold, Cynthia Wetmore, Geoffrey Shapiro. First in human phase 1 dose escalation and expansion study of the safety and pharmacokinetics of the oral CDK7 inhibitor XL102 as a single-agent and in combination therapy in patients with inoperable locally advanced or metastatic solid tumors, including breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-01-02.