Abstract P4-01-35: A Phase 1 Study of the Oral CDK7 Inhibitor XL102 as a Single Agent and in Combination Therapy in Patients With Advanced Solid Tumors (QUARTZ-101): Initial Results From the Dose-Escalation Stage
Authors: Patnaik Amita , Barve Minal , Bhave Manali , Subbiah Vivek , Rasco Drew , Bhatt Aarohi , Li Jing , Andrianova Svetlana , Shapiro Geoffrey 
Published: March 2023

Background: Cyclin-dependent kinase 7 (CDK7) plays a significant role in the cell cycle via activation of CDKs 1, 2, 4, and 6, and regulates transcription via phosphorylation of RNA polymerase II and the estrogen receptor. CDK7 overexpression has been reported in several tumor types, including hormone receptor-positive breast cancer (HR+ BC), triple-negative BC (TNBC), small-cell lung cancer, and epithelial ovarian cancer (EOC). In all major BC subtypes, CDK7 overexpression is associated with poor prognosis. XL102 is a potent, orally bioavailable, highly selective covalent CDK7 inhibitor. QUARTZ-101 is a first-in-human, open-label trial (NCT04726332) evaluating the safety, tolerability, and optimal dose of XL102 as a single agent and in combination regimens in patients with solid tumors, with expansion in subsequent tumor cohorts of advanced HR+ BC, TNBC, EOC, and metastatic castration-resistant prostate cancer (mCRPC). Presented here are initial results from the dose-escalation stage for single-agent XL102 (cohort A). Methods: In the single-agent dose-escalation stage, patients received XL102 orally at multiple dose levels (DLs) using a modified interval 3+3 design: once daily at 20 mg (DL A1), 40 mg (DL A2), 80 mg (DL A3), and 120 mg (DL A4); and twice daily at 40 mg (DL A5). Eligible patients had confirmed inoperable, locally advanced, metastatic, or recurrent solid tumors and ECOG performance status (PS) of 0 or 1; any CNS disease must have been adequately treated and stable for ≥4 weeks. Patients with previous exposure to XL102 or other selective CDK7 inhibitors were excluded, as were patients with uncontrolled, significant intercurrent or recent illness. Prior use of CDK4/6 inhibitors was allowed. The primary objective of dose escalation was to determine the maximum tolerated dose (MTD) and/or recommended dose (RD) of XL102; secondary objectives included safety and tolerability, pharmacokinetics (PK), and drug-drug interactions. Results: At data cutoff of May 13, 2022, twenty patients with various advanced solid tumors (100% stage IV) were enrolled in dose-escalation stage cohort A and treated with single-agent XL102 (DL A1 n=3; A2 n=3; A3 n=7; A4 n=4; A5 n=3). Median age was 67 (range 43–84) years, 85% were female, and 75% had an ECOG PS of 1. Six patients remained on XL102 including 2 treated for &gt;6 months with stable disease, both had received prior CDK4/6 inhibitors (HR+BC and liposarcoma). There were no dose-limiting toxicities at any DL, and MTD/RD has not been determined. Treatment-emergent adverse events (TEAEs) occurred in 95% of patients, with 4 (20%) grade 3 and 0 grade 4 TEAEs; there were no grade 5 treatment-related AEs. Treatment discontinuations were mostly due to radiographic progression (n=8); longest treatment duration was 6.7+ months and ongoing. XL102 demonstrated rapid absorption with a Tmax of approximately 1–2 h and elimination half-life of 5– 8 h. Target occupancy was exposure-dependent and prolonged relative to XL102 PK, consistent with covalent binding to CDK7. Conclusions: Single-agent XL102 was well tolerated at the DLs tested. Updated data, as well as PK results, will be presented. Expansion cohorts in HR+BC, TNBC, EOC, and mCRPC will be initiated once a recommended dose for the expansion-cohort stage is determined.

Citation Format: Amita Patnaik, Minal Barve, Manali Bhave, Vivek Subbiah, Drew Rasco, Aarohi Bhatt, Jing Li, Svetlana Andrianova, Geoffrey Shapiro. A Phase 1 Study of the Oral CDK7 Inhibitor XL102 as a Single Agent and in Combination Therapy in Patients With Advanced Solid Tumors (QUARTZ-101): Initial Results From the Dose-Escalation Stage [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-35.