Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53

Primary Outcome Measures

1. Phase 1a: To assess safety and tolerability of ASTX295 including determination of maximum tolerated dose (MTD), and/or recommended dose for expansion (RDE) to Phase 1b. [ Time Frame: From the date of the first dose until 30 days after discontinuation of study treatment. ]The safety and tolerability will be based on Incidence and severity of treatment-emergent adverse events (AEs) including serious adverse events (SAEs) and dose limiting toxicities (DLTs)
2. Phase 1b: To determine the recommended Phase 2 dose (RP2D) and regimen of ASTX295 to proceed to Phase 2. [ Time Frame: From the date of the first dose until 30 days after discontinuation of study treatment, an average of 6 months to 1 year. ]The RP2D will be based on incidence and severity of AEs, including SAEs and will be determined by the data and safety review committee (DSRC).
3.  

Secondary Outcome Measures

1. Phase 1: To evaluate the preliminary clinical activity of ASTX295 as assessed by disease control rate (DCR). [ Time Frame: From the date of the first dose until Week 16 ]DCR will be calculated as the number of subjects whose response at Week 16 is CR, PR, or stable disease, divided by the total number of subjects evaluable for DCR analysis.
2. Phase 1: To evaluate the preliminary clinical activity as assessed by objective response rate (ORR) of ASTX295. [ Time Frame: From the date of the first dose until study treatment discontinuation, an average of 6 months to 1 year. ]ORR will be calculated as the number of subjects whose best response is CR or PR, divided by the total number of subjects evaluable for ORR analysis.
3. Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (area under the curve [AUC]). [ Time Frame: Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days). ]ASTX295 plasma concentration AUC
4. Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (minimum ocncentration [Cmin]). [ Time Frame: Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days). ]ASTX295 plasma minimum concentration
5. Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (maximum concentration [Cmax]). [ Time Frame: Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days). ]ASTX295 plasma maximum concentration
6. Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (time to reach maximum concentration [Tmax]). [ Time Frame: Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days). ]The time to reach maximum concentration of ASTX295 in plasma.
7. Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (elimination half-life [t½]). [ Time Frame: Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days). ]The elimination half-life (t½) of ASTX295 in plasma.

Inclusion Criteria

1. Participant must be 18 years of age or older, at the time of signing the informed consent.
2. Have histologically or cytologically confirmed advanced solid tumors that are metastatic or unresectable and are refractory or have relapsed after treatment with standard available therapies or for whom standard life-prolonging measures are not available.
3. Documented wild-type TP53 gene status.
4. Have an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 2.
5. Acceptable bone marrow function, as evidenced by the following laboratory data:
   1. Absolute neutrophil count (ANC) ≥1500 cells/mm3
   2. Platelet count ≥100,000 cells/mm3
   3. Hemoglobin >9 g/dL
6. Adequate hepatic function as evidenced by:
   1. Serum total bilirubin ≤1.5 × upper limit of normal (ULN).
   2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×upper limit of normal (ULN) (≤ 3 ULN in the presence of liver metastases).
   3. Serum creatinine ≤1.5 × ULN OR calculated creatinine clearance (by the standard Cockcroft-Gault formula) of ≥50 mL/min or measured glomerular filtration rate of ≥50 mL/min.
7. Participant can be male or femaleInformed Consent
8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol, and willing to participate in the study.Participants are eligible to be included in Phase 1 Part B of the study only if all of the following additional criteria apply:
9. In Phase 1 Part B (dose expansion) of the protocol, subjects must have disease lesions that are amenable to biopsy and must agree and be able to undergo a pre- and on- treatment biopsy.Participants are eligible to be included in Phase 2 of the study only if all of the following additional criteria apply:
10. There is confirmed availability of sufficient tumor specimen either from archival formalin-fixed, paraffin embedded (FFPE) tissue or tissue obtained by a fresh biopsy for analyzing TP53 at a central laboratory.

Exclusion Criteria

1. Poor medical risk in the investigator’s opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.
2. Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator’s opinion, could compromise subject safety, or the integrity of study outcomes, or interfere with the absorption or metabolism of ASTX295.
3. History of, or at risk for, cardiac disease, as evidenced by any of the following conditions:
   1. Abnormal left ventricular ejection fraction.
   2. Congestive cardiac failure of ≥Grade 3.
   3. Unstable cardiac disease.
   4. History or evidence at Screening of long QT interval corrected for heart rate (QTcF), ventricular arrhythmias, clinically significant bradyarrhythmias, third-degree atrioventricular (AV) block, presence of cardiac pacemaker or defibrillator, or other clinically significant arrhythmias.
   5. Screening 12-lead electrocardiogram (ECG) with measurable QTcF interval of ≥470 msec. (Fridericia’s formula should be used).
4. Known advanced human immunodeficiency virus (HIV) infection (including AIDS): clinical stage ≥ 3 according to WHO classification and/or HIV-associated immunodeficiency (CD4 count less than 500 per mm3 of blood). Antiretroviral therapy (ART) is allowed (subjects should be on established ART for at least four weeks and have an HIV viral load less than 400 copies/mL prior to enrollment).
5. Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (Inactive Hepatitis Carrier and subjects with laboratory evidence of no active replication on antivirals – viral load below limit of detection- will be permitted).
6. Known brain metastases, unless previously treated and clinically stable for at least 4 weeks with or without steroids.
7. Known significant mental illness or other conditions, such as active alcohol or other substance abuse that, in the opinion of the investigator, predispose the subject to high risk of noncompliance with the protocol treatment or assessments.
8. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX295), as follows:
   1. Cytotoxic chemotherapy within 3 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) must be stabilized or resolved to ≤Grade 1.
   2. Monoclonal antibodies, biologics, or immunotherapy within 4 weeks prior. Any encountered treatment-related toxicities must be stabilized or resolved to ≤Grade 1.
   3. Molecularly targeted drug or other investigational drugs, without the potential for delayed toxicity, within 4 weeks of the first dose of study treatment or 5 half-lives (minimum 14 days), whichever is shorter. Any encountered treatment-related toxicities must be stabilized or resolved to ≤Grade 1.
   4. Major surgery or radiation within 4 weeks prior to first dose (palliative radiotherapy to a single lesion within 2 weeks).
9. Prior treatment with MDM2 antagonist
10. Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to ASTX295.
11. Active malignancy other than the cancer under study (excludes low risk prostate cancer, basal cell carcinoma of the skin and superficial bladder cancer).