Background: CTX-712 is a first in class, orally available, highly potent and selective small-molecular inhibitor of CDC2-like kinase (CLK), a key regulator of the RNA splicing process that plays a critical role in driving cell growth. CTX-712 demonstrated potent inhibition of proliferation in a variety of human tumor cell lines in vitro and elicited robust antitumor activity in vivo in multiple xenograft models. The objectives of this study are to determine the recommended dose (RD) by evaluating maximum tolerated dose (MTD) and dose limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) profiles, and preliminary efficacy of CTX-712 in patients with solid tumors (ST) and hematologic malignancies (HM). Methods: This study consists of ST and HM dose escalation cohorts to identify MTD and ST dose expansion cohort to identify RD. The ST dose escalation cohort was initiated with accelerated titration and then switched to a 3+3 design (10, 20, 40, 70, 105, 140 and 175 mg/body twice a week in 28-day cycles). The initial dose of HM dose escalation cohort was decided from the safety information of ST dose escalation cohort. A 3+3 design was used in HM dose escalation cohort. Results: As of Dec. 31, 2021, 30 patients were enrolled (16 in the ST dose escalation cohort (10/20/40/70 mg [1], 105/175 mg [3], 140 mg [6]), 10 in the ST expansion cohort, and 4 in the HM dose escalation cohort). In the ST dose escalation cohorts, DLTs were observed in 2 patients (140 mg [platelet count decreased, hypokalemia], 175 mg [dehydration]) and MTD was determined to be 140 mg. Based on this safety information, the ST dose expansion cohort and the HM dose escalation cohort were initiated with the dose of 105 mg twice a week. Among all enrolled patients, the common any-grade Adverse Events (AEs) (≥30%) were nausea (97%), vomiting (63%), diarrhoea (63%), decreased appetite (57%), blood creatinine increased (40%), dysgeusia (37%), constipation (33%), pyrexia (33%) and white blood cell count decreased (30%). The most common Grade 3 or higher AEs were hypokalemia (10%), amylase increased and platelet count decreased (7%). In PK analysis, a dose-dependent increase in systemic exposure of CTX-712 was observed. PD response was assessed in RNA extracted from peripheral blood cells. Dose dependent increases of exon skipping in two marker RNAs were detected. Two Partial Responses and two Complete Responses were observed in ST and HM, respectively. Conclusions: CTX-712 demonstrated an acceptable safety profile with early signs of clinical antitumor activity, establishing the initial proof of concept of the CLK inhibitor. Observed DLTs included dehydration, platelet count decreased, and hypokalemia. Investigation is ongoing to determine RD. Clinical trial information: JapicCTI-184188.