A first-in-human trial of selective CDK7 inhibitor Q901, in patients with advanced solid tumors: Interim results of a phase I study (QRNT-009).

Abstract

Background: Q901 is a potent, covalently binding CDK7 inhibitor with excellent specificity for CDK7 against other protein kinases. Transcriptional regulation by CDK7 inhibition in cancer cells leads to DNA damage repair response inhibition and increased genomic instability. Q901 also regulates cell cycle checkpoints by inhibiting T-loop phosphorylation and transcriptionally downregulating CDK1, 2 and 4. In preclinical in vivo models, intravenous (iv) administration of Q901 once a week and once every three-week dosing regimen was well tolerated and showed significant antitumor activity. The safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy data for 18, 36 and 60 mg/m2 are presented. Methods: QRNT-009 (NCT05394103) is an ongoing Phase 1/2 multicenter, open-label, dose escalation and expansion study. Q901 is administered iv once weekly for four weeks, then once every two weeks thereafter in patients with advanced or metastatic ovarian cancer, castration-resistant prostate cancer (CRPC), breast cancer, endometrial cancer, colorectal cancer, small cell lung cancer (SCLC), or pancreatic cancers. Results: As of data cutoff (12Jan2024), 17 patients received Q901 across 3 dose levels: 5 patients at 18 mg/m2, 4 patients at 36 mg/m2, and 8 patients at 60 mg/m2. The median prior lines of systemic therapy were 4 (range 2 - 17). Of 17 patients who received Q901 across all doses, there were no treatment related SAEs, treatment discontinuations, or dose reductions. Most common TRAEs ≥ 15% were nausea (29.4%), anemia (23.6%) and fatigue (23.5%). As of data cutoff, no DLTs were observed. All plasma PK analyses across dose levels showed dose dependent increase of AUC0-last and Cmax. No major metabolite was observed. POLR2A, which is a CDK7 target engagement marker showed biologically effective change starting from 18 mg/m2. 1 patient with pancreatic cancer who received 18 mg/m2 had a partial response with CA19-9 reduction from 4,632 to 219. 2 patients at 18 mg/m2 and 2 patients at 36 mg/m2 had stable disease. Additional safety and efficacy data will be presented. Conclusions: Preliminary data from QRNT-009 study showed that selective CDK7 inhibitor Q901 is well tolerated. Preliminary antitumor activity and pharmacodynamic observations are encouraging. Dose escalation is ongoing to identify MTD or recommended dose for further studies. Clinical trial information: NCT05394103. © 2024 by American Society of Clinical Oncology