UAMS - Translational Research Institute

l: General 1. Participant must be able to give signed, written informed consent. 2. Participant must have histologically confirmed, locally advanced (i.e., not amenable to curative surgery and/or radiation therapy) or metastatic cancer that has progressed during or after at least 1 prior therapeutic regimen. 3. Participant must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria (by local Investigator) (Eisenhauer, 2009). Participant must have radiographic evidence of disease progression based on RECIST criteria following the most recent line of treatment. Biochemical recurrence (eg, CA-125 in ovarian carcinoma) only is not considered as disease progression. 4. Participant must be willing to provide tissue from a newly obtained tumor biopsy from an accessible tumor lesion not previously irradiated after signed informed consent. Newly obtained is defined as a specimen obtained up to 6 weeks prior to initiation of treatment on Day 1 if no intercurrent systemic therapy in the interval. 5. Participant must be willing to provide an archival tumor tissue block or at least 20 unstained slides, if available. 6. Participant must have stabilized or recovered (Grade 1 or baseline) from all prior therapy related toxicities, except as follows: - Alopecia is accepted. - Endocrine events from prior immunotherapy stabilized at ≤ Grade 2 due to need for replacement therapy are accepted (including hypothyroidism, diabetes mellitus, or adrenal insufficiency). - Neuropathy events from prior cytotoxic therapies stabilized at ≤ Grade 2 are accepted. 7. Participant must have an Eastern Cooperative Oncology Group Performance Status 0 or 1. 8. Participant must have an estimated life expectancy of longer than 3 months. 9. Participant must have adequate organ function at Screening, defined as: - Absolute neutrophil count > 1500 cells/µL without growth factor support within 1 week prior to obtaining the hematology values at Screening. - Hemoglobin ≥ 9.0 g/dL without transfusion or growth factor support within 2 weeks prior to obtaining the hematology values at Screening. - Platelets ≥ 100,000 cells/µL without transfusion within 1 week prior to obtaining the hematology values at Screening. - Calculated creatinine clearance ≥ 30 mL/min as calculated by the Cockcroft Gault formula. - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); ≤ 5 × ULN if liver metastases are present. - Total bilirubin ≤ 1.5 × ULN not associated with Gilbert's syndrome. If associated with Gilbert's syndrome ≤ 3 x ULN is acceptable. - Serum albumin ≥ 3 g/dL. 10. Participant must have adequate coagulation profile as defined below (including if receiving anticoagulation therapy): Prothrombin time within 1.5 x ULN. Activated partial thromboplastin time within 1.5 x ULN. If the patient is anticoagulated, must be on a stable dose of anticoagulant for ≥ 1 month. Tumor Specific Inclusion Criteria For Ovarian Carcinoma: 1. Participant must have histologically documented, platinum resistant, advanced (metastatic and/or unresectable) high-grade serous/endometrioid ovarian, primary peritoneal, or fallopian tube cancer. Platinum-resistant disease, defined as progression or relapse within 6 months after the completion of platinum-based therapy, is eligible. Platinum sensitive disease, defined as disease which progress after 6 or more months after the completion of platinum-based therapy and primary platinum refractory disease, defined as progression while on the upfront platinum-based therapy, is not eligible. a. Carcinosarcoma is eligible. 2. Participant must have received at least 1 but no more than 6 prior lines of systemic therapy, including at least 1 line of therapy containing platinum derivative and taxane, and single-agent therapy must be appropriate as the next line of treatment: 3. Participant must have had prior bevacizumab or did not receive bevacizumab based on Investigator judgment (see Section 2.1.1). For Endometrial Carcinoma 1. Participant must have histologically documented, high-grade endometrial adenocarcinoma. 1. All Grade 3 International Federation of Gynecology and Obstetrics epithelial endometrial histologies are eligible including: endometrioid, serous, and clear-cell carcinoma. 2. Carcinosarcoma is eligible. Enrollment of participants with this histology will be capped at 5% for each cohort. 3. Participant must have no more than 3 prior lines of therapy in the recurrent setting, including platinum-based chemotherapy for subtypes of endometrial adenocarcinoma where it is a standard of care. 2. Participant must have documented failure or ineligibility (based on Investigator judgement) for prior anti-programmed cell death protein 1/anti-programmed death- ligand 1 (PD 1/PD L1) based therapy for advanced/metastatic disease. Prior combination of PD 1/PD L1 inhibitor and vascular endothelial growth factor tyrosine kinase inhibitor is acceptable. For Urothelial Carcinoma 1. Participant must have histologically documented, advanced (metastatic and/or unresectable) urothelial carcinoma. Variant histology is allowed as long as the tumor is predominantly urothelial. 2. Participants must have: 1. Received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant, or adjuvant setting. If platinum was administered in the adjuvant/neoadjuvant setting, participant must have progressed within 12 months of completion. 2. Failed or have been ineligible for checkpoint inhibitors (including PD-1 or PD-L1 inhibitors). 3. Failed or have been ineligible for enfortumab vedotin. 4. Have no known life-prolonging therapy available

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 had a failure to recover from the reversible effects of prior anti-cancer therapy, as follows: 1. Endocrine events from prior immunotherapy at Grade > 2. 2. Neuropathy events from prior cytotoxic therapies at Grade > 2. 3. All other reversible effects of prior anti- cancer therapy (except alopecia) at Grade >1 or Baseline. 3. Participant had systemic therapy or radiation therapy within 2 weeks prior to the first dose of study drug. 4. Participants has known human immunodeficiency virus, hepatitis B, or hepatitis C infection that is considered uncontrolled based on the criteria included in Appendix 2. 5. Participant has a history of clinically meaningful coagulopathy, bleeding diathesis. 6. 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 (QTc) > 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). 7. Participant has a history of major surgery within 4 weeks of Screening. 8. Participant has a history of bowel obstruction requiring decompression through a nasogastric tube within 8 weeks of Screening. Participants has signs or symptoms of intestinal obstruction, which include nausea, vomiting, and objective radiologic finding of bowel obstruction. 9. Participant has taken a prior cell cycle CHK1 inhibitor, including ACR-368 Tumor Specific Exclusion Criteria For Ovarian Carcinoma: 1. Participant has non-epithelial carcinoma, clear-cell, mucinous, germ-cell, low-grade serous, or low-grade endometrioid carcinoma. 2. Participant has a history of clinically meaningful ascites, defined as a history of paracentesis or thoracentesis within 4 weeks of Screening. Participant has a planned therapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1 dosing. 3. Participant has a history of active inflammatory bowel disease within 2 years prior to Screening. 4. Participant has a history of bowel perforation, fistula, necrosis, or leak within 8 weeks of Screening. For Endometrial Adenocarcinoma: 1. Participant has low-grade endometrioid carcinoma. 2. Participant has mesenchymal tumors of the uterus. 3. Participant has a history of clinically meaningful ascites, defined as a history of paracentesis or thoracentesis within 4 weeks of Screening. Participant has a planned therapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1 dosing. For Urothelial Carcinoma: 1. Participant has sarcoma, carcinosarcoma, melanoma, or lymphoma of the bladder. 2. Participant has not received a previous platinum-based regimen. 3. Participant has small cell or neuroendocrine histology.