ACR-368, a CHK1/2 Kinase Inhibitor, in Patients With Relapsed or Refractory Desmoplastic Small Round Cell Tumor: Phase I/II Trial Results

Abstract

Purpose: We hypothesized that ACR-368 (prexasertib) would be active in desmoplastic small round cell tumor (DSRCT) because of favorable responses in preclinical models.

Methods: 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.

Results: 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).

Conclusion: The RP2D of ACR-368 with irinotecan by age group is ACR-368 105 or 150 mg/m² once on day 1 (>21 years or ≤21 years, respectively) and irinotecan 15 mg/m² 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.

FIG 1.

Desmoplastic small round cell tumor in vitro and in vivo models are sensitive to ACR-368. (A) Results from a large-scale screen of DNA-damage response and chemotherapeutic agents are depicted as a heat map using relative viability as a fraction of a negative control and confirm the sensitivity of DSRCT cell lines to Chk1/2 inhibitor ACR-368. (B) A cell line–derived xenograft model showed complete and sustained response to ACR-368 15 mg/kg administered subcutaneously twice daily for 3 days on followed by 4 days of rest. IHC analyses reveal reduction in Ki67 and induction of cleaved caspase 3/7 in tumors treated with ACR-368 for 21 days. (C) Three unique patient-derived xenograft models showed exquisite sensitivity to treatment with ACR-368 using the same schedule described in (B), with sustained regression even after withdrawal of ACR-368 after 28 days of therapy. DSRCT, desmoplastic small round cell tumor.

FIG 2.

CONSORT diagram. i, irinotecan; PD, progressive disease; PR, partial response by RECIST criteria; SD, stable disease; T, temozolomide.

FIG 3.

Tumor responses in patients with DSRCT. (A) Waterfall plot depicting best volumetric tumor response while receiving ACR-368 and irinotecan treatment, stratified by previous irinotecan and no previous irinotecan exposure. (B) Spider plot depicting volumetric tumor response over time (weeks) while receiving ACR-368 and irinotecan. (C and D) PFS and OS of clinical trial enrollees. DSRCT, desmoplastic small round cell tumor; OS, overall survival; PFS, progression-free survival.

FIG A1.

Successful management of myelosuppression because of ACR-368 with growth factors. (A) Neutropenic and (B) thrombocytopenic nadirs experienced in a single patient after exposure to ACR-368 were successfully managed with pegfilgrastim administration at approximately day 5 of each cycle and romiplostim administered once a week.