A First-In-Human, Phase 1 Study Evaluating Oral TACC3 PPI Inhibitor, AO-252, in Advanced Solid Tumors

Inclusion Criteria:

1. Adults ≥ 18 years of age. Patient has TNBC; OR platinum-resistant HGSOC, primaryperitoneal cancer, and/or fallopian-tube cancer; OR serous endometrial cancer, asdescribed below.

2. TNBC:

3. Histologically or cytologically confirmed metastatic or locally recurrentunresectable TNBC per American Society of Clinical Oncology-College of AmericanPathologists (ASCO-CAP) criteria.

4. TNBC must have TP53 mutation/loss and be relapsed/refractory to at least 1 lineof systemic chemotherapy in the metastatic setting (excluding neoadjuvant oradjuvant chemotherapies) or be intolerant of existing therapy(ies). Priorexposure to an immune checkpoint inhibitor is allowed.

5. Platinum-resistant HGSOC, primary peritoneal cancer, and/or fallopian-tube cancer:

6. Histologically or cytologically confirmed diagnosis of metastatic orunresectable HGSOC, with TP53 mutation/loss, with platinum resistance definedas progression during or within 6 months of a platinum containing regimen, withno other standard treatment option available. Prior exposure toplatinum-resistant recurrence therapy is allowed.

7. Patients whose tumors have progressed after at least 1 line of therapy foradvanced/metastatic settings.

8. Systemic therapy with a PARP inhibitor will be counted as 1 line of therapy.Induction followed by maintenance will be counted as 1 line of therapy.

9. Serous endometrial cancer: a. Histologically or cytologically confirmed diagnosis of metastatic or recurrentunresectable serous endometrial cancer with TP53 mutation/loss and tumor must haverelapsed/be refractory to at least 1 line of systemic therapy (including immunecheckpoint inhibitors) but no more than 4 lines of systemic therapy in themetastatic/recurrent setting or be intolerant of existing therapy(ies) known toprovide clinical benefit for their condition.

10. Measurable disease per RECIST v1.1

11. Adequate bone marrow reserve, cardiac, liver, and renal function: a. Absolute neutrophil count (ANC) ≥ 1,500/mm3 b. Platelet count ≥ 100,000/mm3 c.Hemoglobin ≥ 9 g/dL d. Bilirubin ≤ 1.5 × upper limit of normal (ULN) or directbilirubin ≤ ULN for patients with total bilirubin levels >1.5 × ULN e. Alanineaminotransferase (ALT, SGPT) and aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present) f. INR ≤ 1.5 × ULN unless patient isreceiving anticoagulant therapy and PT or aPTT is within therapeutic range ofintended use of anticoagulants g. Creatinine clearance ≥ 60 mL/min (by CockroftGault formula).

12. 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.

13. Sterilization

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

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

16. 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.

17. Life expectancy of ≥ 3 months.

18. Ability to provide written informed consent.

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

Exclusion Criteria:

1. Patients with untreated or symptomatic brain metastases and/or leptomeningealdisease (exception: treated and stable brain metastases without symptoms for ≥ 2weeks after completion of treatment, image documentation is required, and thepatient must not be taking steroids).

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 usingFridericia'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 orbaseline.

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 inducerswithin 14 days or 5 half-lives (whichever is shorter) prior to the administration ofstudy drug.