A Study of ACR-368 in Ovarian Carcinoma, Endometrial Adenocarcinoma, and Urothelial Carcinoma

Inclusion Criteria: General

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

2. Participant must have histologically confirmed, locally advanced (i.e., not amenableto curative surgery and/or radiation therapy) or metastatic cancer that hasprogressed during or after at least 1 prior therapeutic regimen.

3. Participant must have at least 1 measurable lesion per RECIST v1.1 criteria (bylocal Investigator) (Eisenhauer, 2009) in a baseline tumor imaging that has beenobtained within 28 days of the treatment start. Participant must have radiographicevidence of disease progression based on RECIST v1.1 criteria following the mostrecent line of treatment. Biochemical recurrence (eg, cancer antigen [CA-125] inovarian carcinoma) only is not considered as disease progression.

4. Participant must be willing to provide tissue from a newly obtained tumor biopsyfrom an accessible tumor lesion not previously irradiated after written informedconsent. Newly obtained is defined as a specimen taken after written informed consent isobtained, during the 28-day Screening period.

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

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

7. Alopecia is accepted.

8. Endocrine events from prior immunotherapy stabilized at ≤ Grade 2 due to needfor replacement therapy are accepted (including hypothyroidism, diabetesmellitus, or adrenal insufficiency).

9. Neuropathy events from prior cytotoxic therapies stabilized at ≤ Grade 2 areaccepted.

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

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

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

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

15. Hemoglobin ≥ 9.0 g/dL without transfusion or growth factor support within 2weeks prior to obtaining the hematology values at Screening.

16. Platelets ≥ 100,000 cells/µL without transfusion within 1 week prior toobtaining the hematology values at Screening.

17. Calculated creatinine clearance ≥ 30 mL/min as calculated by the CockcroftGault formula.

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

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

20. Serum albumin ≥ 3 g/dL.

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

22. Prothrombin time within 1.5 x ULN.

23. Activated partial thromboplastin time within 1.5 x ULN.

Tumor Specific Inclusion Criteria

For Ovarian Carcinoma:

1. Participant must have histologically documented, advanced metastatic and/orunresectable) platinum resistant high-grade serous/endometrioid ovarian, primaryperitoneal, or fallopian tube cancer. Platinum-resistant disease is defined asprogression or relapse within 6 months after the completion of platinum-basedtherapy. a. Carcinosarcoma is eligible.

2. Participant must have received at least 1 but no more than 6 prior lines of systemictherapy, including at least 1 line of therapy containing platinum derivative andtaxane, 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 onInvestigator judgment (see Section 2.1.1).

4. Participants with or without documented test results assessing alterations in theDNA repair pathway genes, eg, Breast Cancer gene 1 (BRCA1), BRCA2, and homologousrecombination deficiency, at Screening are eligible. Subjects with known BRCAmutated tumors should have received a PARP inhibitor maintenance or treatment.

5. Participant will be enrolled regardless of tumoral folate receptor alpha (FRα)expression status. FRα expression status will be collected for retrospectiveanalysis, if the information is available.

For Endometrial Carcinoma

1. Participant must have histologically documented, high-grade endometrialadenocarcinoma.

2. All Grade 3 International Federation of Gynecology and Obstetrics epithelialendometrial histological subtypes are eligible including: endometrioid, serous,and clear-cell carcinoma.

3. Carcinosarcoma is eligible.

4. Participant must have no more than 4 prior lines of therapy in the recurrentsetting, including platinum-based chemotherapy for subtypes of endometrialadenocarcinoma where it is a standard of care. The four lines of therapies mustnot include more than 3 lines containing a cytotoxic regimen.

5. Participant must have documented failure (includes treatment discontinuation relatedto toxicity) or ineligibility (based on Investigator judgement) for prioranti-programmed cell death protein 1/anti-programmed death- ligand 1 (anti-PD 1/anti-PD L1) based therapy for advanced/metastatic disease. Prior combination of PD 1/PD L1 inhibitor and vascular endothelial growth factor tyrosine kinase inhibitor (TKI) is acceptable.

6. Prior neoadjuvant or adjuvant chemotherapy included in initial treatment are notconsidered first- or later-line treatment unless such treatments were completed lessthan 6 months prior to the current tumor recurrence. Prior treatment may includechemotherapy, chemotherapy/radiation therapy, and/or consolidation/maintenancetherapy.

7. Prior treatment with hormonal therapy or inhibitors of the mTOR or CDK4/6 pathwaysare not considered a line of therapy in any setting.

For Urothelial Carcinoma

1. Participant must have histologically documented, advanced (metastatic and/orunresectable) urothelial carcinoma. Variant histology is allowed as long as thetumor is predominantly urothelial.

2. Participants must have:

3. Received a platinum containing regimen (cisplatin or carboplatin) in themetastatic/locally advanced, neoadjuvant, or adjuvant setting. If platinum wasadministered in the adjuvant/neoadjuvant setting, participant must haveprogressed within 12 months of completion.

4. Been exposed to or have been ineligible for checkpoint inhibitors (includingPD-1 or PD-L1 inhibitors).

5. Been exposed to or have been ineligible for enfortumab vedotin.

Exclusion Criteria: General

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

2. Participant had systemic therapy or radiation therapy within 2 weeks prior to thefirst dose of study drug.

3. Participants has known human immunodeficiency virus, hepatitis B, or hepatitis Cinfection that is considered uncontrolled based on the criteria included in Appendix

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

6. Participant has cardiovascular disease, defined as:

7. Uncontrolled hypertension defined as blood pressure > 160/90 mmHg at Screeningconfirmed by repeat (medication permitted).

8. History of torsades de pointes, significant Screening electrocardiogram (ECG)abnormalities, including ventricular rhythm disturbances, unstable cardiacarrhythmia requiring medication, pathologic symptomatic bradycardia, leftbundle branch block, second degree atrioventricular (AV) block type II, thirddegree AV block, Grade ≥ 2 bradycardia, uncorrected hypokalemia not amenable tocorrection, congenital long QT syndrome, prolonged QT interval due tomedications, corrected QT based on Fridericia's formula (QTcF) > 450 msec (formen) or > 470 msec (for women).

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

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

11. Participant has a history of bowel obstruction related to the current cancer orparticipant has signs or symptoms of intestinal obstruction, which include nausea,vomiting, or objective radiologic finding of bowel obstruction in the last 4 weeksbefore the start of the treatment.

12. 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-gradeserous, or low-grade endometrioid carcinoma.

2. Participant has a history of clinically meaningful ascites, defined as a history ofparacentesis or thoracentesis within 4 weeks of Screening. Participant has a plannedtherapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1dosing.

3. Participant has a history of active inflammatory bowel disease within 2 years priorto Screening.

4. Participant has a history of bowel perforation, fistula, necrosis, or leak within 8weeks 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 ofparacentesis or thoracentesis within 4 weeks of Screening. Participant has a plannedtherapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1dosing.

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.