Study of ASTX029 in Subjects With Advanced Solid Tumors

Inclusion Criteria:

Participants must fulfill all of the following inclusion criteria.

1. Able to understand and comply with study procedures, understand the risks involvedin the study, and provide written informed consent before any study-specificprocedure is performed.

2. Men or women 18 years of age or older.

3. Participants with histologically or cytologically confirmed advanced solid tumorsthat are metastatic or unresectable, who are refractory or have relapsed aftertreatment with available therapies or for whom standard life-prolonging measures orapproved therapies are not available. In Phase 1 Part B and in the Phase 2 portionof the protocol, participants must also have documented gene alterations in the MAPKpathway as detailed in the protocol.

4. In Phase 1 Part B of the protocol, participants must have disease lesions that areamenable to biopsy.

5. In the Phase 2 portion of the protocol, participants must have measurable diseaseaccording to RECIST v1.1.

6. Eastern Cooperative Oncology Group performance status 0 to 2.

7. Acceptable organ function as evidenced by the following laboratory data:

8. Aspartate aminotransferase (AST) and alanine aminotransferase ≤2×upper limit ofnormal (ULN) or ≤3 ULN in the presence of liver metastases.

9. Total serum bilirubin ≤1.5×ULN.

10. Absolute neutrophil count (ANC) ≥1500 cells/mm3.

11. Platelet count ≥100,000 cells/mm3.

12. Calculated creatinine clearance (by the standard Cockcroft Gault formula) of ≥50 mL/min or glomerular filtration rate of ≥50 mL/min.

13. Women of child-bearing potential (according to recommendations of the Clinical TrialFacilitation Group [CTFG]; see protocol for details) must not be pregnant orbreastfeeding and must have a negative pregnancy test within 24 hours before thefirst dose of study treatment. While receiving study treatment and for at least 5half-lives of ASTX029 or metabolite plus 30 days after completing treatment, womenof child-bearing potential must agree to practice highly effective contraceptivemeasures (as described in the protocol) and must refrain from donating eggs (ova,oocytes) for the purpose of reproduction.

14. Men with female partners of child-bearing potential (according to recommendations ofthe CTFG; see protocol for details) must agree to, during the treatment period andfor at least 5 half-lives of ASTX029 or metabolite plus 90 days after completingtreatment, practice highly effective contraceptive measures (as described in theprotocol), not to father a child, and to refrain from donating sperm.

Exclusion Criteria:

1. Hypersensitivity to ASTX029 or excipients of the drug product.

2. Poor medical risk in the investigator's opinion because of systemic diseases inaddition to the cancer under study, for example, uncontrolled infections.

3. Life-threatening illness, significant organ system dysfunction, or other conditionthat, in the investigator's opinion, could compromise participants safety or theintegrity of study outcomes or interfere with the absorption or metabolism ofASTX029.

4. Prior anticancer treatments or therapies within the indicated time window prior tofirst dose of study treatment (ASTX029), as follows:

5. Cytotoxic chemotherapy or radiotherapy within 3 weeks prior. Palliativeradiotherapy to a single lesion within 2 weeks prior. Any encounteredtreatment-related toxicities (excepting alopecia) not stabilized or resolved to ≤Grade 1.

6. Monoclonal antibodies within 4 weeks prior. Any encountered treatment-relatedtoxicities not stabilized or resolved to ≤Grade 1.

7. Molecularly targeted drug or investigational drugs, without the potential fordelayed toxicity, within 4 weeks of the first dose of study treatment or 5half-lives (minimum 14 days), whichever is shorter. Any encounteredtreatment-related toxicities (excepting alopecia) not stabilized or resolved to ≤Grade 1.

8. Prior treatment with extracellular signal-regulated kinase (ERK) inhibitors.

9. History of, or at risk for, cardiac disease, as evidenced by 1 or more of thefollowing conditions:

10. Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.

11. Congestive cardiac failure of ≥Grade 3 severity according to New York HeartAssociation functional classification defined as patients with markedlimitation of activity and who are comfortable only at rest.

12. Unstable cardiac disease including unstable angina or hypertension as definedby the need for overnight hospital admission within the last 3 months (90days).

13. History or evidence of long QT interval corrected for heart rate (QTc),ventricular arrhythmias including ventricular bigeminy, complete left bundlebranch block, clinically significant bradyarrhythmias such as sick sinussyndrome, second- and third-degree atrioventricular (AV) block, presence ofcardiac pacemaker or defibrillator, or other significant arrhythmias.

14. Screening 12-lead electrocardiogram (ECG) with measurable QTc interval of ≥470msec. (Fridericia's formula should be used to calculate the QTc intervalthroughout the study.)

15. Known history of human immunodeficiency virus (HIV) infection or seropositiveresults consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.

16. Known brain metastases, unless previously treated and stable for at least 3 monthswith or without steroids.

17. Known significant mental illness or other conditions, such as active alcohol orother substance abuse that, in the opinion of the investigator, predispose theparticipant to high risk of noncompliance with the protocol treatment orassessments.

18. History or current evidence/risk of retinal vein occlusion (RVO) or central serousretinopathy (CSR) including:

19. Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma orocular hypertension, uncontrolled diabetes mellitus) or

20. Visible retinal pathology as assessed by ophthalmic examination at screeningthat is considered a risk factor for RVO or CSR such as:

• Evidence of optic disc cupping or
• Evidence of new visual field defects on automated perimetry or
• Intraocular pressure >21 mmHg as measured by tonography.