Phase 1/2 first-in-human (FIH) study of CPI-0209, a novel small molecule inhibitor of enhancer of zeste homolog 2 (EZH2) in patients with advanced tumors.

Abstract

3104 Background: Enhancer of Zeste homolog 2 (EZH2) is a histone methyltransferase and the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). EZH2 is frequently overexpressed in cancers and correlates with poor prognosis. CPI-0209 is an oral, small molecule, second-generation, selective inhibitor of EZH2 designed to achieve comprehensive target coverage through extended on-target residence time. The compound demonstrates more potent anti-tumor activity in preclinical cancer models, compared to first-generation EZH2 inhibitors. CPI-0209 is currently being evaluated in a Phase 1/2, open-label, FIH study (NCT04104776). Methods: Patients (pts) with advanced tumors were enrolled in a 3+3 design. Primary objective is to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CPI-0209. Secondary objectives are to evaluate the safety, PK, and PD in pts who received CPI-0209 QD in 28 days cycles (C). Results: As of December 16, 2020, 33 pts were treated: pancreatic cancer (n = 6), mesothelioma, breast, colorectal, and ovarian cancer (n = 5 each), leiomyosarcoma, melanoma, cholangiocarcinoma, prostate, bladder, endometrial clear cell and gastric cancer (n = 1 each). Pts received CPI-0209 at 50 mg (n = 4), 100 mg, 137.5 mg, and 187.5 mg (n = 6 each), 225 mg (n = 7), and 275 mg (n = 4) daily dose. Median treatment duration was 43 days (range 1-239); 4 pts are ongoing. Median age was 64 yrs (range 24-79); 15 (45%) pts were male. Patients were heavily pretreated, with 67% of pts had ≥ 3 prior lines of therapy. No dose limiting toxicities have been observed. The most frequent treatment-emergent adverse events (TEAEs) (≥10%) were fatigue (27%), diarrhea (24%), nausea (21%), abdominal pain, alopecia, anemia, thrombocytopenia, and dysgeusia (15% each), and vomiting, headache, decreased appetite, and alkaline phosphatase increased (12% each); usually grade 1 or 2 in severity. Thrombocytopenia was dose-dependent and not associated with bleeding or clinical sequalae. Three pts (9%) discontinued CPI-0209 due to TEAEs. Comprehensive target engagement (assessed by global reduction in H3K27me3 levels in monocytes) was observed within the first cycle at all dose levels. CPI-0209 also increased the expression of PRC2-controlled gene sets in blood in a dose-dependent manner. Updated safety, PK, PD, and preliminary efficacy results from Phase 1 will be presented. Conclusions: CPI-0209 achieved robust PD effects and a PK-PD relationship has been established. CPI-0209 monotherapy was generally well tolerated, and treatment related AEs were manageable and reversible. The MTD has not been reached. Clinical trial information: NCT04104776.