Slotkin Emily K, Mauguen Audrey, Dela Cruz Filemon S, Ortiz Michael V, Avutu Viswatej, Meyers Paul A, Wexler Leonard H, O'Donohue Tara J, Kinnaman Michael D, Kelly Ciara M, D'Angelo Sandra P, Keohan Mary Lou, Gounder Mrinal M, Thornton Katherine, Nacev Benjamin A, Chi Ping, Rosenbaum Evan, Dickson Mark, Pachhal Sagarika, Somwar Romel, Ladanyi Marc, Robb Caroline, Pandit-Taskar Neeta, Hwang Sinchun, Price Anita, Behr Gerald, Reed Damon R, Kentsis Alex, Kung Andrew L, Bender Julia Glade, Tap William D
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Oncol Adv. 2025 Apr 28;2(1):e2400095. doi: 10.1200/OA-24-00095. eCollection 2025.
We hypothesized that ACR-368 (prexasertib) would be active in desmoplastic small round cell tumor (DSRCT) because of favorable responses in preclinical models.
Preclinical work identified ACR-368 activity in DSRCT, and a phase I/II trial of ACR-368 and irinotecan in patients 12 months and older with relapsed/refractory DSRCT was conducted. The primary objectives were determination of recommended phase II dose (RP2D) and best overall response rate (ORR) at the RP2D in DSRCT, with ≥3 of 16 responses considered promising.
Preclinical data confirmed ACR-368 as potentially therapeutic in DSRCT, and 19 patients were enrolled in a subsequent clinical trial. Treatment was well tolerated, and cytopenias were managed using growth factors. Fifteen of 19 patients, including five of six achieving PR, had previously received irinotecan. The estimated ORR at the RP2D was 23% (lower boundary one-sided 90% CI, 9%), exceeding the unpromising rate of 5%. In addition, three patients with DSRCT had a PR at doses other than the RP2D, bringing the ORR for all doses (n = 19) to 32% (90% CI, 15% to 53%). The median overall survival was 19 months (95% CI, 13 to 36).
The RP2D of ACR-368 with irinotecan by age group is ACR-368 105 or 150 mg/m once on day 1 (>21 years or ≤21 years, respectively) and irinotecan 15 mg/m once daily for 5 days in 21-day cycles for both groups. The study met its primary objective to consider ACR-368 and irinotecan promising in DSRCT and, to our knowledge, is the first incorporating a targeted therapy to achieve this magnitude of response.
我们假设ACR - 368（prexasertib）对促结缔组织增生性小圆细胞肿瘤（DSRCT）具有活性，因为在临床前模型中有良好反应。
临床前研究确定了ACR - 368在DSRCT中的活性，并对12个月及以上复发/难治性DSRCT患者进行了ACR - 368与伊立替康的I/II期试验。主要目标是确定DSRCT的推荐II期剂量（RP2D）以及RP2D时的最佳总缓解率（ORR），16例缓解中≥3例被认为有前景。
临床前数据证实ACR - 368对DSRCT有潜在治疗作用，19例患者随后参加了临床试验。治疗耐受性良好，血细胞减少症通过生长因子进行处理。19例患者中的15例，包括6例达到PR的患者中的5例，之前接受过伊立替康治疗。RP2D时的估计ORR为23%（单侧90%CI下限，9%），超过了无前景率5%。此外，3例DSRCT患者在非RP2D剂量下达到PR，使所有剂量（n = 19）的ORR达到32%（90%CI，15%至53%）。中位总生存期为19个月（95%CI，13至36）。
按年龄组划分，ACR - 368与伊立替康联合使用的RP2D为：ACR - 368 105或150mg/m²，均在第1天给药一次（分别适用于>21岁或≤21岁患者），两组伊立替康均为15mg/m²，每日一次，共5天，每21天为一个周期。该研究达到了其主要目标，即认为ACR - 368与伊立替康对DSRCT有前景，据我们所知，这是首个纳入靶向治疗并取得如此程度缓解的研究。
