A Phase 2 Study of ACR-368 Therapy in Subjects With Endometrial Cancer

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Overview

ACR-368 (prexasertib; formerly LY2606368) is an investigational, intravenous checkpoint kinase inhibitor being developed primarily for biomarker-selected patients with platinum-resistant ovarian and endometrial cancers, and other solid tumors. It targets CHK1 and CHK2 and is being advanced with a proteomics-based companion diagnostic (OncoSignature). The FDA has granted Fast Track designation for ACR-368 monotherapy in OncoSignature-positive platinum‑resistant ovarian and endometrial cancers, and Breakthrough Device designations for the OncoSignature assays in ovarian and endometrial cancers. (ir.acrivon.com)

Mechanism of action

Prexasertib inhibits CHK1/CHK2, key regulators of S/G2 cell-cycle checkpoints activated by replication stress and DNA damage. Inhibition drives replication catastrophe and mitotic entry with unrepaired DNA, leading to tumor cell death. Pharmacodynamic studies in patients show decreased RAD51 foci and increased γ‑H2AX and other DNA damage markers, consistent with homologous recombination impairment; preclinical work in high‑grade serous ovarian cancer (HGSOC) models demonstrates monotherapy antitumor activity and synergy with PARP inhibition. (aacrjournals.org)

Efficacy

• Ovarian cancer
• BRCA wild‑type, recurrent HGSOC (single‑center phase 2): ORR 29% (8/28, ITT) in heavily pretreated patients; most had platinum‑resistant/refractory disease. (pubmed.ncbi.nlm.nih.gov)
• Multicenter phase 2 across resistant/refractory cohorts (N=169): ORR 12.1% in platinum‑resistant cohorts; 6.9% in platinum‑refractory cohort; disease control rates 37.1% (resistant) and 31.0% (refractory). (pubmed.ncbi.nlm.nih.gov)
• BRCA‑mutant HGSOC, heavily pretreated (phase 2, single‑arm): ORR 11% (2/18 evaluable); most had prior PARP inhibitor exposure. (ascopubs.org)

• Combination with olaparib (phase 1): signals of activity in PARP inhibitor–resistant BRCA‑mutant HGSOC (4/18 partial responses). (aacrjournals.org)

• Endometrial cancer (biomarker‑selected, ongoing)

• Company‑reported, prospective OncoSignature‑positive cohort in a registrational‑intent phase 2b: confirmed ORR 62.5% (95% CI, 30.4–86.5) presented at ESMO 2024; segregation of responses by OncoSignature status reported. Data are preliminary and not yet peer‑reviewed. (ir.acrivon.com)

• Other solid tumors

• Squamous cell carcinomas (phase 1b): single‑agent activity observed; ORR 15% in anal SCC and 5% in head and neck SCC; 3‑month clinical benefit rate 29% across squamous cohorts. (aacrjournals.org)
• Head and neck SCC with radiotherapy combinations (phase 1b): feasibility with cetuximab–RT established (MTD 30 mg/m²); small cohorts showed high radiographic response rates but interpretation limited by size and design. (pubmed.ncbi.nlm.nih.gov)
• Desmoplastic small round cell tumor (DSRCT), prexasertib + irinotecan (phase I/II): estimated ORR 23% at the RP2D (32% across all doses); median OS 19 months. (pubmed.ncbi.nlm.nih.gov)

Safety

Across trials, the predominant toxicities are myelosuppressive: - Very common grade 3/4 neutropenia and leukopenia; thrombocytopenia and anemia also observed. Febrile neutropenia was a dose‑limiting toxicity in combination settings and occurred infrequently as high‑grade events in monotherapy studies. Growth‑factor support is commonly used. (pubmed.ncbi.nlm.nih.gov)

In the chemoradiation head‑and‑neck study, non‑hematologic events consistent with RT/EGFR‑inhibitor combinations (e.g., mucositis/stomatitis, dysphagia, dermatitis) were common. (pubmed.ncbi.nlm.nih.gov)

Notes on ongoing development

Acrivon is conducting a multicenter, registrational‑intent phase 2 program using the ACR‑368 OncoSignature to prospectively select patients; preliminary efficacy signals (including endometrial cancer) have been disclosed by the sponsor and require independent peer‑review. The ACR‑368 program holds FDA Fast Track status, while the companion OncoSignature assays hold FDA Breakthrough Device designations (tests are investigational and not approved). (ir.acrivon.com)

Further reading

• Lee et al. Prexasertib in BRCA wild‑type recurrent HGSOC (phase 2, Lancet Oncology 2018). (pubmed.ncbi.nlm.nih.gov)
• Colombo et al. Phase 2 study in platinum‑resistant/refractory ovarian cancer (Gynecologic Oncology Reports 2022). (pubmed.ncbi.nlm.nih.gov)
• Do et al. Phase 1 prexasertib + olaparib with pharmacodynamic analyses (Clinical Cancer Research 2021). (aacrjournals.org)
• Colevas et al. Phase 1b in squamous cell carcinomas (Clinical Cancer Research 2018). (aacrjournals.org)
• Desmoplastic small round cell tumor phase I/II (prexasertib + irinotecan) results (JCO 2025). (pubmed.ncbi.nlm.nih.gov)
• Trial design and regulatory designations for OncoSignature‑guided phase 2 program (company communications; interpret with caution). (acrivon.com)

Last updated: Oct 2025

Inclusion Criteria: General

1. Participant must be able to give signed, written informed consent.

2. Participant must have histologically documented, high-grade endometrial cancer.

3. Treatment History Requirements:

1. Subject must have received prior platinum-based chemotherapy

2. Subject must have received prior anti-PD-(L)1 therapy

4. Participant must have histologically confirmed metastatic cancer that has progressed during or after at least 1 prior therapeutic regimen.

5. Participant must have at least 1 measurable lesion per RECIST v1.1 criteria (by local Investigator) in a baseline tumor imaging that has been obtained within 28 days of the treatment start. Participant must have radiographic evidence of disease progression based on RECIST v1.1 criteria following the most recent line of treatment.

6. Arm 1 and 2 only: Participant must be willing to provide tissue from a newly obtained tumor biopsy from an accessible tumor lesion not previously irradiated after written informed consent.

Newly obtained is defined as a specimen taken after written informed consent is obtained, during the 28-day Screening period.

7. Participant must be willing to provide an archival tumor tissue block or at least 20 unstained slides, if available.

8. Participant must have stabilized or recovered (Grade 1 or baseline) from all prior therapy related toxicities, except as follows:

1. Alopecia is accepted.

2. Endocrine events from prior immunotherapy stabilized at ≤ Grade 2 due to need for replacement therapy are accepted (including hypothyroidism, diabetes mellitus, or adrenal insufficiency).

3. Neuropathy events from prior cytotoxic therapies stabilized at ≤ Grade 2 are accepted.

9. Participant must have an Eastern Cooperative Oncology Group Performance Status 0 or 1.

10. Participant must have an estimated life expectancy of longer than 3 months.

11. Participant must have adequate organ function at Screening, defined as:

1. Absolute neutrophil count \> 1500 cells/µL without growth factor support within 1 week prior to obtaining the hematology values at Screening.

2. Hemoglobin ≥ 9.0 g/dL.

3. Platelets ≥ 150,000 cells/µL without transfusion within 1 week prior to obtaining the hematology values at Screening.

4. Calculated creatinine clearance (CrCl) ≥ 50 mL/min as calculated by the Cockcroft-Gault formula.

5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); ≤ 5 × ULN if liver metastases are present.

6. Total bilirubin ≤ 1.5 × ULN not associated with Gilbert's syndrome. If associated with Gilbert's syndrome ≤ 3 x ULN is acceptable.

7. Serum albumin ≥ 3 g/dL.

12. Participant must have adequate coagulation profile as defined below if not on anticoagulation. If subject is receiving anticoagulation therapy, then subject must be on a stable dose of anticoagulation for ≥ 1 month:

1. Prothrombin time within 1.5 x ULN.

2. Activated partial thromboplastin time within 1.5 x ULN.

Exclusion Criteria: General

1. Participant with known symptomatic brain metastases requiring \> 10 mg/day of prednisolone (or its equivalent). Participants with previously diagnosed brain metastases are eligible if they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to the start of ACR-368 treatment, fulfill the steroid requirement for these metastases, and are neurologically stable based on central nervous system imaging ≥ 4 weeks after treatment.

2. Participant has mesenchymal tumors of the uterus.

3. Participant has a history of clinically meaningful ascites, defined as history of paracentesis or thoracentesis with therapeutic intent, within 4 weeks of Screening. Subjects with planned therapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1 dosing are excluded.

4. Participant had systemic therapy or radiation therapy within 3 weeks prior to the first dose of study drug.

5. Participants has known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is considered uncontrolled based on the criteria included in Appendix 2.

6. Participant has a history of clinically meaningful coagulopathy, bleeding diathesis.

7. Participant has cardiovascular disease, defined as:

1. Uncontrolled hypertension defined as blood pressure \> 160/90 mmHg at Screening confirmed by repeat (medication permitted).

2. History of torsades de pointes, significant Screening electrocardiogram (ECG) abnormalities, including ventricular rhythm disturbances, unstable cardiac arrhythmia requiring medication, pathologic symptomatic bradycardia, left bundle branch block, second degree atrioventricular (AV) block type II, third degree AV block, Grade ≥ 2 bradycardia, uncorrected hypokalemia not amenable to correction, congenital long QT syndrome, prolonged QT interval due to medications, corrected QT based on Fridericia's formula (QTcF) \> 450 msec (for men) or \> 470 msec (for women).

3. Symptomatic heart failure (per New York Heart Association guidelines; (Caraballo, 2019), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction \< 20%, transient ischemic attack, or cerebrovascular accident within 6 months of Day 1).

8. Participant has a history of major surgery within 4 weeks of Screening.

9. Participant has experienced bowel obstruction related to the current cancer within the last 6 months or signs or symptoms of intestinal obstruction, which include nausea, vomiting, or objective radiologic finding of bowel obstruction in the last 4 weeks before the start of the treatment.

10. Participant has taken a prior cell cycle CHK1 inhibitor, including ACR-368