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

Eligibility 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:
• 5. Measurable disease per RECIST v1.1
• 6. Adequate bone marrow reserve, cardiac, liver, and renal function:
• 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.
• 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):
• 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.