This study is a first-in-human, open-label, multicenter, Phase 1-2 study to assess the
safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of ASTX029
administered orally to subjects with advanced solid malignancies who are not candidates for
approved or available therapies.
ASTX029 is a synthetic small molecule inhibitor of extracellular signal-regulated kinases
(ERKs) 1/2. ASTX029 has not been previously evaluated in human subjects. The Phase 1 portion
of this study will assess safety and determine the maximum tolerated dose, the recommended
Phase 2 dose (RP2D), and the recommended dosing regimen of ASTX029 administered orally. The
Phase 2 portion will assess preliminary clinical activity in tumors characterized by gene
aberrations in the mitogen-activated protein kinase (MAPK) signal pathway that may confer
sensitivity to ASTX029.
Subjects must fulfill all of the following inclusion criteria.
1. Able to understand and comply with study procedures, understand the risks involved in
the study, and provide written informed consent before any study-specific procedure is
2. Men or women 18 years of age or older.
3. Subjects with histologically or cytologically confirmed advanced solid tumors that are
metastatic or unresectable, who are refractory or have relapsed after treatment with
available therapies or for whom standard life-prolonging measures or approved
therapies are not available. In Phase 1 Part B (except in the potential food-effect
cohort) and in the Phase 2 portion of the protocol, subjects must also have documented
gene alterations in the MAPK pathway as detailed in the protocol.
4. In Phase 1 Part B (except in the potential food-effect cohort) of the protocol,
subjects must have disease lesions that are amenable to biopsy.
5. In the Phase 2 portion of the protocol, subjects must have measurable disease
according 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:
1. Aspartate aminotransferase and alanine aminotransferase ≤2×upper limit of normal
(ULN) or ≤3 ULN in the presence of liver metastases.
2. Total serum bilirubin ≤1.5×ULN.
3. Absolute neutrophil count ≥1500 cells/mm3.
4. Platelet count ≥100,000 cells/mm3.
5. Calculated creatinine clearance (by the standard Cockcroft Gault formula) of ≥50
mL/min or glomerular filtration rate of ≥50 mL/min.
8. Women of child-bearing potential (according to recommendations of the Clinical Trial
Facilitation Group as detailed in the protocol) must not be pregnant or breastfeeding
and must have a negative pregnancy test at screening. Women of child-bearing potential
and men with female partners of child-bearing potential must agree to practice 2
highly effective contraceptive measures (as described in the protocol) during the
study and for at least 3 months after completing treatment and must agree not to
become pregnant or father a child while receiving study treatment and for at least 3
months after completing treatment.
1. Hypersensitivity to ASTX029 or excipients of the drug product.
2. Poor medical risk in the investigator's opinion because of systemic diseases in
addition to the cancer under study, for example, uncontrolled infections.
3. 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 ASTX029.
4. Prior anticancer treatments or therapies within the indicated time window prior to
first dose of study treatment (ASTX029), as follows:
1. Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered
treatment-related toxicities (excepting alopecia) not stabilized or resolved to
2. Monoclonal antibodies within 4 weeks prior and any encountered treatment-related
toxicities not resolved to ≤Grade 1.
3. Molecularly targeted drug or 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.
5. Prior treatment with ERK inhibitors.
6. History of, or at risk for, cardiac disease, as evidenced by 1 or more of the
1. Abnormal left ventricular ejection fraction (<50%) on echocardiogram or
multiple-gated acquisition scan.
2. Congestive cardiac failure of ≥Grade 3 severity according to New York Heart
Association functional classification defined as patients with marked limitation
of activity and who are comfortable only at rest.
3. Unstable cardiac disease including unstable angina or hypertension as defined by
the need for overnight hospital admission within the last 3 months (90 days).
4. History or evidence of long QT interval corrected for heart rate (QTc),
ventricular arrhythmias including ventricular bigeminy, complete left bundle
branch block, clinically significant bradyarrhythmias such as sick sinus
syndrome, second- and third-degree atrioventricular block, presence of cardiac
pacemaker or defibrillator, or other significant arrhythmias.
5. Screening 12-lead electrocardiogram with measurable QTc interval of ≥470 msec.
(Fridericia's formula should be used to calculate the QTc interval throughout the
7. Known history of human immunodeficiency virus infection or seropositive results
consistent with active hepatitis B virus or active hepatitis C virus infection.
8. Known brain metastases, unless previously treated and stable for at least 3 months
with or without steroids.
9. 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.
10. History or current evidence/risk of retinal vein occlusion (RVO) or central serous
retinopathy (CSR) including:
1. Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or
ocular hypertension, uncontrolled diabetes mellitus) or
2. Visible retinal pathology as assessed by ophthalmic examination at screening that
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.