A First-In-Human, Phase 1 Study Evaluating Oral TACC3 PPI Inhibitor, AO-252, in Advanced Solid Tumors With or Without Brain Metastases

Inclusion Criteria:

1. Adults ≥ 18 years of age.

2. Patient has histologically or cytologically confirmed metastatic or locally advancedunresectable solid tumors with TP53 mutation/loss and with/without brain metastasis.Patients must have relapsed/be refractory to at least 1 line of systemic therapy inthe metastatic setting (excluding melanoma).

3. Prostate cancer:

4. mCRPC with histologic confirmation of adenocarcinoma. mCRPC with neuroendocrinefeatures or mixed histology are excluded

5. Patients will be enrolled irrespective of the TP53 status

6. Participant must have prostate specific antigen (PSA) of ≥ 2 ng/mL

7. Is surgically or medically castrated, with testosterone levels of less than 50ng/dL

8. Patients who progressed on at least 1 prior novel androgen receptor AR-targetedtherapy (that is, abiraterone acetate, apalutamide, enzalutamide,darolutamide), and or at least 1 prior systemic chemotherapy (e.g., docetaxel)

9. Solid tumors with brain metastasis:

10. Histologically or cytologically confirmed metastatic or locally advancedunresectable solid tumors excluding melanoma with TP53 mutation/loss and tumormust have relapsed/be refractory to at least 1 line of systemic therapy.Untreated brain metastases not requiring immediate local CNS therapy

11. Previously treated brain metastases with progression of previous lesions or newlesions, but not requiring immediate local CNS therapy

12. At least one measurable untreated brain lesion ≥0.5 cm and <3.0 cm in thelongest axis

13. Prior SRS radiosurgery (must be completed within 7 days of study treatmentinitiation) is allowed as long as the previous treatment volume does notoverlap with the current targets.

14. Measurable disease per RECIST v1.1 criteria. For mCRPC patients, tumor response willbe evaluated using RECIST version 1.1 (soft tissue) and PCWG-3 criteria (bone) andefficacy endpoints will also include radiographic progression-free survival (rPFS),PSA50 response and PSA progression

15. Adequate bone marrow reserve, cardiac, liver, and renal function:

16. Absolute neutrophil count (ANC) ≥ 1,500/mm3

17. Platelet count ≥ 100,000/mm3

18. Hemoglobin ≥ 9 g/dL

19. Bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤ ULN forpatients with total bilirubin levels >1.5 × ULN

20. Alanine aminotransferase (ALT, SGPT) and aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present)

21. INR ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy and PT oraPTT is within therapeutic range of intended use of anticoagulants

22. Creatinine clearance ≥ 60 mL/min (by Cockroft Gault formula).

23. Female patients of child-bearing potential must have a negative serum pregnancy testand use at least 1 form of acceptable birth control method listed below as approvedby the Investigator before initiating study treatment and for 3 months after thelast dose of study drug.

24. Sterilization

25. Any hormonal contraceptives (non-CYP 3A4 inhibitors) associated with inhibitionof ovulation

26. IUD (intrauterine device) or intrauterine hormone releasing system

27. Male patients must be sterilized or use a form of barrier contraception, such ascondoms with spermicide, during the study and for 3 months after the last dose ofstudy drug.

28. Life expectancy of ≥ 3 months.

29. Ability to provide written informed consent.

30. An Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.

Exclusion Criteria:

1. Patients with symptomatic brain metastases requiring treatment and/or leptomeningealdisease

2. Patients with a previous history of another malignancy (other than cured basal cellor squamous cell carcinoma of the skin or cured in-situ carcinoma) within 3 years ofstudy entry.

3. Patients with uncontrolled pleural effusions, pericardial effusion, or ascites thatdo not resolve.

4. Patients with gastrointestinal tract disease causing the inability to take oralmedication (e.g., swallowing difficulties, malabsorption syndromes, extensive smallbowel resection [> 100cm], gastric bypass surgery).

5. Pregnant or breast-feeding patients or any patient with child-bearing potential notusing adequate contraception.

6. Known human immunodeficiency virus, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (excluding cured HBV and/or cured HCV infection).

7. Presence of any serious concomitant systemic disorders incompatible with the studyin the opinion of the Investigator (e.g., uncontrolled congestive heart failure,active infection).

8. Radiation therapy to > 30% of bone marrow within 3 months before study entry.

9. Patients with clinically significant autoimmune disease, either currently present ofpresent within 2 years, including a current requirement for systemicimmunosuppressive therapy equivalent to > 10 mg/prednisone daily (localimmunosuppressive therapy such as inhaled or topical corticosteroids is allowed).

10. Patients with abnormal or clinically significant electrocardiogram (ECG) abnormality, including but not limited to a confirmed corrected QT interval using Fridericia's formula (QTcF) > 470 msec.

11. Patient has received systemic anticancer therapy within 3 weeks or 5 half-lives, whichever is shorter.

12. Patients must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline.

13. Any of the following conditions (on-study testing is not required):

a. Known HIV-infected patients unless on effective anti-retroviral therapy with an undetectable viral load within 6 months and no opportunistic infection within the past 12 months, or b. Known or suspected hepatitis B if active infection (patients with chronic hepatitis B infection must have an undetectable HBV viral load on suppressive therapy, if indicated; positive surface antibody alone is not an exclusion), or c. Known or suspected hepatitis C infection that has not been treated and cured unless currently on treatment with an undetectable viral load.

15. Administration of strong or moderate cytochrome (CYP) 3A4 inhibitors and inducers within 14 days or 5 half-lives (whichever is shorter) prior to the administration of study drug.