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

• Adults ≥ 18 years of age.
• Patient has histologically or cytologically confirmed metastatic or locally advanced unresectable 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 in the metastatic setting (excluding melanoma).
• Prostate cancer:
• mCRPC with histologic confirmation of adenocarcinoma. mCRPC with neuroendocrine features or mixed histology are excluded
• Patients will be enrolled irrespective of the TP53 status
• Participant must have prostate specific antigen (PSA) of ≥ 2 ng/mL
• Is surgically or medically castrated, with testosterone levels of less than 50 ng/dL
• Patients who progressed on at least 1 prior novel androgen receptor AR-targeted therapy (that is, abiraterone acetate, apalutamide, enzalutamide, darolutamide), and or at least 1 prior systemic chemotherapy (e.g., docetaxel)
• Solid tumors with brain metastasis:
• Histologically or cytologically confirmed metastatic or locally advanced unresectable solid tumors excluding melanoma with TP53 mutation/loss and tumor must have relapsed/be refractory to at least 1 line of systemic therapy. Untreated brain metastases not requiring immediate local CNS therapy
• Previously treated brain metastases with progression of previous lesions or new lesions, but not requiring immediate local CNS therapy
• At least one measurable untreated brain lesion ≥0.5 cm and <3.0 cm in the longest axis
• Prior SRS radiosurgery (must be completed within 7 days of study treatment initiation) is allowed as long as the previous treatment volume does not overlap with the current targets.
• Measurable disease per RECIST v1.1 criteria. For mCRPC patients, tumor response will be evaluated using RECIST version 1.1 (soft tissue) and PCWG-3 criteria (bone) and efficacy endpoints will also include radiographic progression-free survival (rPFS), PSA50 response and PSA progression
• Adequate bone marrow reserve, cardiac, liver, and renal function:
• Absolute neutrophil count (ANC) ≥ 1,500/mm3
• Platelet count ≥ 100,000/mm3
• Hemoglobin ≥ 9 g/dL
• Bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 × ULN
• Alanine aminotransferase (ALT, SGPT) and aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present)
• INR ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy and PT or aPTT is within therapeutic range of intended use of anticoagulants
• Creatinine clearance ≥ 60 mL/min (by Cockroft Gault formula).
• 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.
• Sterilization
• Any hormonal contraceptives (non-CYP 3A4 inhibitors) associated with inhibition of ovulation
• IUD (intrauterine device) or intrauterine hormone releasing system
• 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.
• Life expectancy of ≥ 3 months.
• Ability to provide written informed consent.
• An Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.

Exclusion Criteria

• Patients with symptomatic brain metastases requiring treatment and/or leptomeningeal disease
• 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.
• Patients with uncontrolled pleural effusions, pericardial effusion, or ascites that do not resolve.
• 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).
• Pregnant or breast-feeding patients or any patient with child-bearing potential not using adequate contraception.
• Known human immunodeficiency virus, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (excluding cured HBV and/or cured HCV infection).
• 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).
• Radiation therapy to > 30% of bone marrow within 3 months before study entry.
• 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).
• 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.
• Patient has received systemic anticancer therapy within 3 weeks or 5 half-lives, whichever is shorter.
• Patients must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline.
• 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.
• 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.