An open-label, single-arm, dose escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of the ATR inhibitor SC0245 in advanced solid malignancies.
Authors: Gong Ji-fang , Sun Yuping , Wu Xiaohua , Zhang Jian , Guo Hai-jun , Su Rong , Wang Sheng , Li Chun-lai , Zhang Li-qin , Li Shi-chang , Wang Yi-wei , Hei Yong-Jiang , Shen Lin 
Published: August 2024

e15126 Background: Ataxia telangiectasia and Rad3-related (ATR) is a critical protein that senses DNA damage and is an integral part of the DNA damage repair pathway.SC0245, a novel and orally administered small molecule ATR inhibitor, is being developed for advanced solid malignancies. In vitro, SC0245 is highly potent against the ATR/ATRIP(h) enzyme with IC50 values ranging from 14 to 43 nM and has potent antiproliferative activity against a wide range of human cancers. This is the first report of an ongoing first-in-human study of SC0245 monotherapy in patients (pts) with advanced solid malignancies. Methods: An accelerated titration design was used to increase doses in the first two dose levels (40mg and 80mg once daily (QD) continuous, 21 days/cycle) followed by a standard “3+3” design in the remainder of the study (continuous schedule: 120mg and 160mg QD, 21 days/cycle; or intermittent schedule: 200mg, 240mg, 300mg QD, 160mg, 200mg and 260mg twice daily (BID), 3 days on and 4 days off, repeat every week x 4 weeks, 28 days/cycle). Tumor assessments are being performed every 8 weeks using RECIST v1.1. Results: As of the data cut-off-date of January 10, 2024, 27 pts (median age, 56; male, 48.1%) were enrolled and treated with SC0245 doses of 1, 1, 4, 4, 4, 2, 4, 3 and 4 pts in 40, 80, 120, 160, 200, 240 and 300mg QD, and 160 and 200mg BID cohort, respectively. No DLTs have been observed to date. Most TEAEs have been Grade 1 or 2 in severity. TEAEs experienced in ≥25% pts include: leukopenia and thrombocytopenia (9/27, 33.3%, each), and anemia, increased conjugated bilirubin and constipation (8/27, 29.6%, each). There were no ≥ Grade 3 TEAEs experienced in more than 2 pts. There were neither dose adjustment nor treatment discontinuation due to TRAEs. Eleven of 21 pts who were evaluable for tumor assessment had stable disease as their best response, with seven pts having reductions in target lesions. The PK characteristics of SC0245 indicated fast oral absorption (median Tmax, 0.5~2.0 h), a long half-life (mean t1/2,16.1~36.4 h) and high intersubject variability. The relationship between SC0245 exposure and dose was nonlinear with minimal accumulation after cumulative treatment in some pts. Additionally, SC0245 exposure and relevant PK parameters have reached the range associated with efficacy in preclinical studies. Conclusions: SC0245 exhibited favorable safety and PK characteristics when administered intermittently at doses up to 200mg BID in pts with advanced solid cancers. SC0245 appeared to induce less hematological toxicity than other ATR inhibitors at relevant doses. Based on these preliminary data, SC0245 will be developed in combination with other anti-tumor agents that may have synergies with ATR inhibitors such as topoisomerase 1 inhibitors and DNA damaging agents. Clinical trial information: CTR20210769.