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

The purpose of this study is to assess the safety, tolerability and efficacy of the study drug AO-252 and identify the best dose for use in future studies.

The purpose of this study is to characterize the safety, tolerability including determination of maximum tolerated dose (MTD), and identify the recommended Phase 2 dose (RP2D). The study will also look at pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of AO-252 as a monotherapy in participants with advanced or metastatic triple negative breast cancer (TNBC), high- grade serous ovarian carcinoma (HGSOC), and endometrial cancer

Eligibility Criteria:
Inclusion Criteria:

1. Adults ≥ 18 years of age. Patient has TNBC; OR platinum-resistant HGSOC, primary peritoneal cancer, and/or fallopian-tube cancer; OR serous endometrial cancer, as described below.
2. TNBC:

   1. Histologically or cytologically confirmed metastatic or locally recurrent unresectable TNBC per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria.
   2. TNBC must have TP53 mutation/loss and be relapsed/refractory to at least 1 line of systemic chemotherapy in the metastatic setting (excluding neoadjuvant or adjuvant chemotherapies) or be intolerant of existing therapy(ies). Prior exposure to an immune checkpoint inhibitor is allowed.
3. Platinum-resistant HGSOC, primary peritoneal cancer, and/or fallopian-tube cancer:

   1. Histologically or cytologically confirmed diagnosis of metastatic or unresectable HGSOC, with TP53 mutation/loss, with platinum resistance defined as progression during or within 6 months of a platinum containing regimen, with no other standard treatment option available. Prior exposure to platinum-resistant recurrence therapy is allowed.
   2. Patients whose tumors have progressed after at least 1 line of therapy for advanced/metastatic settings.
   3. 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.
4. Serous endometrial cancer:

   a. Histologically or cytologically confirmed diagnosis of metastatic or recurrent unresectable serous endometrial cancer with TP53 mutation/loss and tumor must have relapsed/be refractory to at least 1 line of systemic therapy (including immune checkpoint inhibitors) but no more than 4 lines of systemic therapy in the metastatic/recurrent setting or be intolerant of existing therapy(ies) known to provide clinical benefit for their condition.
5. Measurable disease per RECIST v1.1
6. 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 direct bilirubin ≤ ULN for patients with total bilirubin levels \>1.5 × ULN e. Alanine aminotransferase (ALT, SGPT) and aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present) f. INR ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy and PT or aPTT is within therapeutic range of intended use of anticoagulants g. Creatinine clearance ≥ 60 mL/min (by Cockroft Gault formula).
7. Female patients of child-bearing potential must have a negative serum pregnancy test and use at least 1 form of acceptable birth control method listed below as approved by the Investigator before initiating study treatment and for 3 months after the last dose of study drug.

   1. Sterilization
   2. Any hormonal contraceptives (non-CYP 3A4 inhibitors) associated with inhibition of ovulation
   3. IUD (intrauterine device) or intrauterine hormone releasing system
8. Male patients must be sterilized or use a form of barrier contraception, such as condoms with spermicide, during the study and for 3 months after the last dose of study drug.
9. Life expectancy of ≥ 3 months.
10. Ability to provide written informed consent.
11. An Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.

Exclusion Criteria:

1. Patients with untreated or symptomatic brain metastases and/or leptomeningeal disease (exception: treated and stable brain metastases without symptoms for ≥ 2 weeks after completion of treatment, image documentation is required, and the patient must not be taking steroids).
2. Patients with a previous history of another malignancy (other than cured basal cell or squamous cell carcinoma of the skin or cured in-situ carcinoma) within 3 years of study entry.
3. Patients with uncontrolled pleural effusions, pericardial effusion, or ascites that do not resolve.
4. Patients with gastrointestinal tract disease causing the inability to take oral medication (e.g., swallowing difficulties, malabsorption syndromes, extensive small bowel resection \[\> 100cm\], gastric bypass surgery).
5. Pregnant or breast-feeding patients or any patient with child-bearing potential not using 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 study in 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 of present within 2 years, including a current requirement for systemic immunosuppressive therapy equivalent to \> 10 mg/prednisone daily (local immunosuppressive therapy such as inhaled or topical corticosteroids is allowed).

11. 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.

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

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

14. 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.