A First-In-Human, Phase 1 Study Evaluating Oral TACC3 PPI Inhibitor, AO-252, in Advanced Solid Tumors
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
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
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1: Dose Escalation Participants will be assigned to dose levels. |
Drug: AO-252
AO-252 will be administered oral tablets daily
|
| Experimental: Part 2: Dose Expansion After doses are decided in Part 1, participants entering part 2 will be assigned to a dose level. |
Drug: AO-252
AO-252 will be administered oral tablets daily
|
Outcome Measures
Primary Outcome Measures
- Safety Assessments [Dose escalation] [12 months]
Incidence of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects
- Safety Assessments [Dose escalation] [12 months]
Identify the maximum tolerated dose and the doses for expansion
- Safety Assessments [Dose escalation and Dose expansion] [30 months]
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
- Safety Assessments [Dose escalation and Dose expansion] [30 months]
Number of participants with Treatment-related Adverse Events (AEs) graded per NCI-CTCAE version 5.0
- Safety Assessments [Dose escalation and Dose expansion] [30 months]
Number of participants with Treatment-Emergent AEs (TEAEs) graded per NCI-CTCAE version 5.0
- Safety Assessments [Dose escalation and Dose expansion] [30 months]
Number of participants with Dose Interruptions and Permanent Treatment Discontinuations
Secondary Outcome Measures
- Antitumor Activity of AO-252 [Dose escalation and Dose expansion] [30 months]
Determine the objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- Antitumor Activity of AO-252 [Dose escalation and Dose expansion] [30 months]
Determine the disease control rate (DCR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- Antitumor Activity of AO-252 [Dose escalation and Dose expansion] [30 months]
Determine the time to response (TTR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Antitumor Activity of AO-252 [Dose escalation and Dose expansion] [30 months]
Determine the time to progression (TTP) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- Pharmacokinetic Profile of AO-252 [Dose escalation and Dose expansion] [30 months]
Identity the maximum concentration (Cmax) on Day 1 of Cycle 1-3 and D14 and 28 of Cycle 1
- Pharmacokinetic Profile of AO-252 [Dose escalation and Dose expansion] [30 months]
Identify the area under the curve (AUC) on Day 1 of Cycle 1-3 and D14 and 28 of Cycle 1
- Pharmacokinetic Profile of AO-252 [Dose escalation and Dose expansion] [30 months]
Identify the time to maximum concentration (Tmax) on Day 1 of Cycle 1-3 and D14 and 28 of Cycle 1
Eligibility Criteria
Criteria
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.
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TNBC:
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Histologically or cytologically confirmed metastatic or locally recurrent unresectable TNBC per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria.
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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.
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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.
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Platinum-resistant HGSOC, primary peritoneal cancer, and/or fallopian-tube cancer:
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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.
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Patients whose tumors have progressed after at least 1 line of therapy for advanced/metastatic settings.
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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.
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Serous endometrial cancer:
- 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.
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Adequate bone marrow reserve, cardiac, liver, and renal function:
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Absolute neutrophil count (ANC) ≥ 1,500/mm3
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Platelet count ≥ 100,000/mm3
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Hemoglobin ≥ 9 g/dL
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Bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 × ULN
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Alanine aminotransferase (ALT, SGPT) and aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present)
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INR ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy and PT or aPTT is within therapeutic range of intended use of anticoagulants
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Serum creatinine ≤ ULN or creatinine clearance ≥ 60 mL/min (by Cockroft Gault formula).
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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.
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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.
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Life expectancy of ≥ 3 months.
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Ability to provide written informed consent.
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An Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
Exclusion Criteria:
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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).
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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.
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Patients with uncontrolled pleural effusions, pericardial effusion, or ascites that do not resolve.
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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).
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Pregnant or breast-feeding patients or any patient with child-bearing potential not using adequate contraception.
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Known human immunodeficiency virus, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (excluding cured HBV and/or cured HCV infection).
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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).
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Radiation therapy to > 30% of bone marrow before study entry.
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Patients who require chronic systemic steroid therapy (> 10 mg prednisone daily or equivalent) or those that are on any other form of immunosuppressive medication.
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Patients with active autoimmune disease or with a documented history of autoimmune disease.
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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.
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Patient has received systemic anticancer therapy within 3 weeks or 5 half-lives, whichever is shorter.
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Patients must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline.
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Any of the following conditions (on-study testing is not required):
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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
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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
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Known or suspected hepatitis C infection that has not been treated and cured unless currently on treatment with an undetectable viral load.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Oklahoma Univeristy | Oklahoma City | Oklahoma | United States | 73104 |
| 2 | The University of Texas M.D. Anderson Cancer Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- A2A Pharmaceuticals Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- A2A-O-004