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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, Endometrial Cancer

Intervention / Treatment
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* Drug: AO-252


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. TNBC: Histologically or cytologically confirmed metastatic or locally recurrent unresectable TNBC per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria. 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. Disease must have progressed on no more than 4 prior lines of systemic therapy for locally advanced or metastatic disease (not including adjuvant or neo-adjuvant). Systemic therapy with a PARP inhibitor will be counted as 1 line of therapy. Platinum-resistant HGSOC, primary peritoneal cancer, and/or fallopian-tube cancer: 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. Patients whose tumors have progressed after at least 1 line of therapy for advanced/metastatic settings. 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. 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. 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 Serum creatinine ≤ ULN or 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 contraception as approved by the Investigator before initiating study treatment and for 3 months after the last dose of study drug. Male patients must use a form of barrier contraception approved by the Investigator 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 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). 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 before study entry. Patients who require chronic systemic steroid therapy (> 10 mg prednisone daily or equivalent) or those that are on any other form of immunosuppressive medication. Patients with active autoimmune disease or with a documented history of autoimmune disease. 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): 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 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 Known or suspected hepatitis C infection that has not been treated and cured unless currently on treatment with an undetectable viral load. Administration of cytochrome (CYP) 3A4 inhibitors and inducers within 14 days or 5 half-lives (whichever is shorter) prior to the administration of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation<br>Participants will be assigned to dose levels. | Drug: AO-252<br>* AO-252 will be administered oral tablets daily<br>|
| Experimental: Part 2: Dose Expansion<br>After doses are decided in Part 1, participants entering part 2 will be assigned to a dose level. | Drug: AO-252<br>* AO-252 will be administered oral tablets daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Assessments [Dose escalation] | Incidence of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects | 12 months | 
| Safety Assessments [Dose escalation] | Identify the maximum tolerated dose and the doses for expansion | 12 months | 
| Safety Assessments [Dose escalation and Dose expansion] | Number of participants with Serious Adverse Events (SAEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 | 30 months | 
| Safety Assessments [Dose escalation and Dose expansion] | Number of participants with Treatment-related Adverse Events (AEs) graded per NCI-CTCAE version 5.0 | 30 months | 
| Safety Assessments [Dose escalation and Dose expansion] | Number of participants with Treatment-Emergent AEs (TEAEs) graded per NCI-CTCAE version 5.0 | 30 months | 
| Safety Assessments [Dose escalation and Dose expansion] | Number of participants with Dose Interruptions and Permanent Treatment Discontinuations | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor Activity of AO-252 [Dose escalation and Dose expansion] | Determine the objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 30 months | 
| Antitumor Activity of AO-252 [Dose escalation and Dose expansion] | Determine the disease control rate (DCR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 30 months | 
| Antitumor Activity of AO-252 [Dose escalation and Dose expansion] | Determine the time to response (TTR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | 30 months | 
| Antitumor Activity of AO-252 [Dose escalation and Dose expansion] | Determine the time to progression (TTP) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 30 months | 
| Pharmacokinetic Profile of AO-252 [Dose escalation and Dose expansion] | Identity the maximum concentration (Cmax) on Day 1 of Cycle 1-3 and D14 and 28 of Cycle 1 | 30 months | 
| Pharmacokinetic Profile of AO-252 [Dose escalation and Dose expansion] | Identify the area under the curve (AUC) on Day 1 of Cycle 1-3 and D14 and 28 of Cycle 1 | 30 months | 
| Pharmacokinetic Profile of AO-252 [Dose escalation and Dose expansion] | Identify the time to maximum concentration (Tmax) on Day 1 of Cycle 1-3 and D14 and 28 of Cycle 1 | 30 months |