Conditions: Solid Tumor, Adult
Keywords: Neoplasms Solid Tumors Antineoplastic Agents MAPK ERK
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 192
Healthy volunteers: no

Brief summary:
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 participants with advanced solid malignancies who are not candidates for approved or available therapies.

Detailed description:
ASTX029 is a synthetic small molecule inhibitor of extracellular signal-regulated kinases (ERKs) 1/2. ASTX029 has not been previously evaluated in human participants. 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.

Arms:
arm 1: Participants received ASTX029 10 milligrams (mg), powder in bottle (PiB), orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fed state. arm 2: Participants received ASTX029 20 mg, PiB, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fed state. arm 3: Participants received ASTX029 60 mg, PiB, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fed state. arm 4: Participants received ASTX029 120 mg, PiB, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fed state. arm 5: Participants received ASTX029 200 mg, orally, PiB, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fed state. arm 6: Participants received ASTX029 80 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fed state. arm 7: Participants received ASTX029 120 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fed state. arm 8: Participants received ASTX029 40 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fasted state. arm 9: Participants received ASTX029 80 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fasted state. arm 10: Participants received ASTX029 120 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fasted state. arm 11: Participants received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fasted state. arm 12: Participants received ASTX029 280 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fasted state. arm 13: Participants received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fasted state. arm 14: Participants with neuroblastoma RAS (NRAS)-mutant melanoma received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months. arm 15: Participants with Kirsten RAS (KRAS)-mutant or KRAS-amplified non-small cell lung cancer (NSCLC) received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months. arm 16: Participants with B isoform of RAF kinase (BRAF) V600-mutant cancers (non-colorectal cancers) received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months. arm 17: Participants with BRAF-fusion cancers received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months. arm 18: Participants with gynecological cancers with alterations in the mitogen-activated protein kinase (MAPK) pathway received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months. arm 19: Participants with tumors that were characterized by other gene aberrations (that upregulate the MAPK signal pathway) received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months.

Interventions: intervention 1: ASTX029 intervention 2: ASTX029
Intervention descriptions: intervention 1: PiB intervention 2: Tablet

Protocol document:
Prot_000.pdf: 
Official Title:      A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 
   in Subjects With Advanced Solid Tumors 
NCT ID:               NCT03520075    
Document Date: Protocol Version 5.0: 24 May 2024


Taiho Oncology, Inc.
ASTX029-01
Protocol ASTX029-01, Amendment 5.0
23 May 2024
Confidential – Proprietary Information
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Clinical Study Protocol — ASTX029-01
A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in 
Subjects With Advanced Solid Tumors
Sponsor:
Taiho Oncology, Inc.
101 Carnegie Center
Suite 101
Princeton, NJ 08540
USA
Medical Monitor:
 MD
(mobile)
E-mail:
Pharmacovigilance Group:
E-mail: drugsafety@taihooncology.com
IND Number:
134813
EudraCT Number:
2018-004568-72
Study Clinical Phase:
Phase 1-2
Version (Date):
Original (11 January 2018)
Amendment 1.0 (21 February 2019)
Amendment 2.0 (12 July 2019)
Amendment 3.0 (31 December 2019)
Amendment 4.0 (21 July 2020)
Amendment 4.1 UK (12 March 2021)
Amendment 4.2 France (08 June 2021)
Amendment 5.0 (23 May 2024)
This clinical study will be conducted in accordance with the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH), Good Clinical Practice (GCP) Guidelines, EU 
CTR536/2014, and applicable regulatory requirements.
Confidentiality Statement
The information contained in this document is the property of Taiho Oncology, Inc. (TOI). This document contains 
strictly confidential information, and no part of this document may be published or disclosed without the prior 
written approval of TOI, except by request from competent authorities.
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SUMMARY OF CHANGES
The rationale for this substantial amendment is to update “Astex Pharmaceuticals, Inc.” and 
associated references to Astex to “Taiho Oncology, Inc.”, “Taiho”, or “the Sponsor”, as a result 
of Astex Pharmaceuticals, Inc. becoming a wholly-owned subsidiary of Taiho Oncology Inc.as 
of 01 January 2024, to insert the addition of the End of Study definition, and to add the Study 
Extension phase. 
In addition to minor edits, the summary of changes for the current amendment are shown in the 
table below:
Section Number and Title
Description of Change
Rationale
Throughout
Sponsor name was changed
Astex Pharmaceuticals, Inc. is now 
a wholly-owned subsidiary of Taiho 
Oncology Inc.as of 1 January 2024.
Section 1.3 Summary of 
Nonclinical and Clinical Data 
for ASTX029/1.3.3 Clinical 
Data and Human 
Pharmacokinetics
Updated with current data available in IB.
Section 4.1 Overall Study 
Design
Updated study duration to 5 years (61 
months and 55 months for recruitment.
Section 4.1.1 Phase 1
Added sentence to report the in vitro 
diagnostic ( IVD) medical devices are 
appropriately registered for use.
Section 4.4 Data and Safety 
Review Committee
Updated: The DSRC composition is 
detailed in the DSRC charter.
Section 5.2 Inclusion Criteria
Updated contraception for #8: must agree 
to contraception requirements for at least 
32 days after last treatment and updated 
the description of contraceptive 
requirements.
Updated contraception for #9: pregnant 
partner of partner who is WOCBP must 
agree to contraception requirements for at 
least 92 days after last treatment and 
updated the description of contraceptive 
requirements.
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Section Number and Title
Description of Change
Rationale
Section 5.4.3 Replacement of 
Subjects
Relocated last sentence to Section 12.
Section 5.4.4 End of Study
Added entire section.
Section 5.4.5 Study 
Extension
Added entire section.
Section 7.1.5 ASTX029 
Administration
Added instruction for missed dose.
Section 7.3Dose-Escalation 
Guidelines and 
Recommended Phase 2 Dose 
Decision
Added statement for the DSRC decision 
of the RP2D.
Section 7.7 Overdose 
Instructions
Updated with name change/department 
and timing.
Section 9.4.9 Schedule of 
Events
Added Table 13 SoE for the Study 
Extension Phase.
Sections 10.2.3 and 10.2.4 
Reporting Requirements for 
Pregnancy and Abortion; 
Serious Adverse Events 
(SAEs)
Due to name change, the department 
name was changed.
Section 12 Study Duration 
and Termination
Updated study duration to 5 years (61 
months and 55 months for recruitment. 
Added deleted sentence from Section 
5.4.3: The Sponsor may stop the study at 
any time. In case of this event, the 
Sponsor will make reasonable efforts to 
ensure subjects are transitioned off study 
in an orderly manner. 
Section 14.2.2 ASTX029 and 
VFR Accountability
Added: Until ASTX029 PiB was phased 
out, initial supplies of VFR were shipped 
to each study center's pharmacy when 
conditions as described above were met.
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PROTOCOL SYNOPSIS
Study Number and Title:
ASTX029-01: A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in 
Subjects With Advanced Solid Tumors
Investigational Drug: ASTX029
Clinical Phase: 1-2
Study Centers Planned/Country: 

Phase 1: up to 14 study centers in the United States and Europe.

Phase 2: up to 30 study centers in North America and Europe.
Study Objectives: 
Primary Objectives

Phase 1 (Parts A and B): To assess safety and to identify the maximum tolerated dose (MTD), the 
recommended Phase 2 dose (RP2D), and the recommended dosing regimen of ASTX029.

Phase 2: To assess preliminary clinical activity, as determined by objective response rate (ORR) in 
tumors characterized by gene aberrations in the mitogen-activated protein kinase (MAPK) signal 
pathway that may confer sensitivity to ASTX029.
Secondary Objectives

To determine the pharmacokinetic (PK) profile of ASTX029 including the food effect on PK 
parameters.

To evaluate other clinical activity parameters, such as duration of response (DOR), disease control 
rate (DCR), progression-free survival (PFS), and overall survival (OS). 

To evaluate relevant pharmacodynamic markers and target engagement (ie, phosphorylated 
ribosomal s6 kinase [pRSK] inhibition) in tumor biopsies. 
Exploratory Objective

To identify and evaluate biomarkers of ASTX029 activity.
Study Design and Investigational Plan: 
This study is a first-in-human (FIH), open-label, multicenter, Phase 1-2 study to assess the safety, PK, 
pharmacodynamics, and preliminary clinical activity of ASTX029 administered orally to subjects 
≥18 years of age with advanced solid malignancies who are not candidates for approved or available 
therapies. 
Phase 1
The Phase 1 portion of the study will consist of Parts A and B as follows:
Part A (Dose Escalation): Dose-escalation stage to identify the MTD for up to 2 dosing regimens of 
ASTX029 and the recommended dose for expansion (RDE), defined as either MTD or a dose below 
MTD that the Data and Safety Review Committee (DSRC) agrees shows adequate safety, PK, and/or 
preliminary biological or clinical activity. Subjects enrolled in Regimen 1 (continuous dosing) will 
receive ASTX029 orally once a day on Days 1 through 21 of each 21-day cycle. If Regimen 2 
(intermittent dosing) is opened to enrollment, subjects enrolled in Regimen 2 will receive ASTX029 
orally once a day on Days 1 through 14 of each 21-day cycle. Initially, subjects will be allocated to 
Regimen 1 (continuous dosing). Subjects in the first cohort of Regimen 1 will receive a flat starting dose 
of 10 mg daily (QD). Planned initial escalation will be 100% (doubling the dose) until 160 mg. Smaller 
increments of dose escalation will be used above 160 mg. Dose doubling will also be discontinued if any 
1 of the following occurs within a cohort:

1 subject experiences a dose-limiting toxicity (DLT).
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
Any study-drug-related clinically significant ≥Grade 2 AE not adequately managed or resolved to 
baseline or Grade 1 by supportive treatment that, per the DSRC, indicates further dose doubling 
would be potentially unsafe for future subjects.

Any study-drug-related AE or confluence of AEs that, per the DSRC, indicates further dose 
doubling would be potentially unsafe for future subjects.
After this point, dose escalation will proceed in smaller increments (eg, by a 50% increase initially and 
an ~25% increase at the higher dose levels over the previous level) after review of all available safety, 
PK, and biomarker data from Cycle 1 in at least 3 subjects and approval by the DSRC. Also, after this 
point, the sponsor, with approval of the DSRC, will determine if Regimen 2 is to be opened for 
enrollment. Randomization to either Regimen 1 or Regimen 2 will begin if both regimens are open for 
enrollment. Should Regimen 2 be evaluated, based on safety and PK data from Regimen 1 and 
depending on the nature, timing, and severity of observed AEs, the dose for the first cohort of subjects 
enrolled to Regimen 2 may be escalated to the next level pending approval by the DSRC. If the MTD is 
reached in 1 regimen before the other regimen, all subsequent subjects will be enrolled, without 
randomization, to the remaining regimen until the MTD is determined for each regimen evaluated. After 
reaching MTD or RDE for Regimens 1 and 2, the DSRC will also advise if it is appropriate to test an 
alternative intermittent regimen (Optional Regimen 3, eg, 7 days on/7 days off) and will recommend the 
dose and dosing regimen to be used. The total dose per cycle for the new regimen will not exceed the 
total safe dose per cycle already established in the first 2 regimens.
The starting dose in each regimen evaluated will be escalated stepwise in successive cohorts of at least 
3 evaluable subjects each with additional allowed expansion to 6 subjects (3+3 study design) until the 
MTD is determined for each regimen. Dose levels and dosing regimens, the number of cohorts, and the 
number of subjects per cohort may be modified, as needed, in response to emerging data and 
recommendations from the DSRC.
Dose-escalation/de-escalation decisions will be based on the occurrence of DLTs during the first cycle 
of each dose level and the recommendations of the DSRC following review of all available safety, PK, 
and biomarker data from the completed first cycle of at least 3 subjects in each cohort. The DSRC RDE 
decision will be based on all available safety, PK, biomarkers, and preliminary activity data from all 
cycles (including potential for late or cumulative toxicity). The DSRC will also advise whether or not it 
is appropriate to proceed to Part B (Dose Expansion).
ASXT029 was originally introduced into the clinic in the powder-in-bottle (PiB) form and administered 
under fed conditions. Protocol Amendment 1.0 introduced the tablet dosage form  when it became 
available. Protocol Amendment 2.0 introduced the evaluation of administration under fasted conditions 
during Phase 1 Part A dose escalation. 
Part B (Dose Expansion): One or more dose levels (and regimens) may be studied in Phase 1 Part B to 
supplement available safety, PK, and/or clinical activity data and to evaluate target engagement in fresh 
tumor tissue biopsies. A total of 14 evaluable subjects will be treated at each dose/regimen selected. If 
more than 1 dose/regimen is selected, subjects will be randomized in a 1:1 ratio. Subjects will have to 
meet the following molecular eligibility criteria: documented activating mutations in BRAF (BRAF 
V600 mutation or activating atypical non-V600 aberrations), KRAS, NRAS, or HRAS. The RP2D 
decision by the DSRC will be based on all available PK, pharmacodynamic, safety, and preliminary 
activity data from all cycles (including the potential for late or cumulative toxicity). The RP2D could be 
the same or lower than the RDE. 
The DSRC will advise when it is appropriate to proceed to Phase 2.
Phase 2
The Phase 2 portion of the study will explore the preliminary single-agent antitumor activity of 
ASTX029 at the RP2D of the selected dosing regimen identified in Phase 1 Parts A and B in tumors 
characterized by gene aberrations in the MAPK signal pathway that may confer sensitivity to ASTX029. 
The Phase 2 part of the study will consist of the following up to 6 cohorts:
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
Cohort A: NRAS-mutant melanoma.

Cohort B: KRAS-mutant or KRAS-amplified non-small cell lung cancer (NSCLC).

Cohort C: BRAF V600-mutant cancers (non-colorectal cancers).

Cohort D: BRAF-fusion cancers. 

Cohort E: Gynecological cancers with alterations in the MAPK pathway.

Cohort F: Tumors characterized by other gene aberrations that upregulate the MAPK signal 
pathway.
In the Phase 2 part of the study, molecular eligibility will be based on the presence of documented gene 
aberrations in MAPK pathway. 
For Phase 2, the sample size is based on a Simon’s Optimal 2-stage design. Each cohort will enroll 
10 subjects into the first stage of Simon’s 2-stage design at the RP2D and the dosing regimen identified 
in Phase 1 Parts A and B. Should ≥2 first-stage subjects respond, an additional 19 subjects will be 
enrolled into the second stage. Therefore, up to 29 subjects will be enrolled into each cohort. 
For Phase 2 Cohort F (which will enroll patients with various tumor types and gene aberrations, the 
sponsor, with approval of the DSRC, may expand enrollment for a particular molecularly defined 
subpopulation in which the most number of responses are observed to 10 or 29 subjects under the same 
Simon’s Optimal 2-stage design as for the other cohorts for better assessment of activity in that disease 
subpopulation (Optional Cohort F Expansion). It is expected that no more than 2 subpopulations will be 
expanded in this manner. 
Study Population: It is anticipated that up to 300 evaluable subjects will be enrolled if the study fully 
enrolls both Phases 1 and 2. This includes approximately 120 evaluable subjects in Phase 1 and up to 
approximately 180 evaluable subjects in Phase 2.
The number of cohorts in Phase 1 Parts A and B and the number of subjects per cohort will be based on 
emerging safety data, PK data, and recommendations from the DSRC. The number of subjects in Phase 
2 will be based on clinical activity observed and recommendations from the DSRC. More subjects may 
be enrolled if more dose levels are tested in Part A, if more than 1 cohort is selected for expansion in 
Part B, or if more than the expected number of subpopulations in Cohort F of Phase 2 are expanded.
Inclusion Criteria
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 performed.
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 
and in the Phase 2 portion of the protocol, subjects must also have documented gene alterations in 
the MAPK pathway.
4.
In Phase 1 Part B 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 Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1.
6.
Eastern Cooperative Oncology Group performance status 0 to 2.
7.
Acceptable organ function, as evidenced by the following laboratory data:
a)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2×upper limit of 
normal (ULN) or ≤3 ULN in the presence of liver metastases.
b)
Total serum bilirubin ≤1.5×ULN.
c)
Absolute neutrophil count (ANC) ≥1500 cells/mm3.
d)
Platelet count ≥100,000 cells/mm3. 
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e)
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 [CTFG]; see protocol for details) must not be pregnant or breastfeeding and must have a 
negative pregnancy test within 24 hours before the first dose of study treatment. While receiving 
study treatment and for at least 32 days (approximately 5 half-lives of ASTX029 or metabolite plus 
30 days after completing treatment, women of child-bearing potential must agree to practice highly 
effective contraceptive measures (as described in the protocol) and must refrain from donating eggs 
(ova, oocytes) for the purpose of reproduction. 
9.
Men with a pregnant partner or nonpregnant partner who is a woman of child-bearing potential 
(according to recommendations of the CTFG; see protocol for details) must agree to, during the 
treatment period and for at least 92 days (approximately 5 half-lives of ASTX029 or metabolite plus 
90 days) after completing treatment, practice highly effective contraceptive measures (as described 
in the protocol), not to father a child, and to refrain from donating sperm.
Exclusion Criteria
Subjects meeting any of the following exclusion criteria will be excluded from the study:
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 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:
a)
Cytotoxic chemotherapy or radiotherapy within 3 weeks prior. Palliative radiotherapy to a single 
lesion within 2 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) 
not stabilized or resolved to ≤Grade 1. 
b)
Monoclonal antibodies or biologics within 4 weeks prior. Any encountered treatment-related 
toxicities not stabilized or resolved to ≤Grade 1.
c)
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 (excepting alopecia) not 
stabilized or resolved to ≤Grade 1.
5.
Prior treatment with extracellular signal-regulated kinase (ERK) inhibitors. 
6.
History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:
a)
Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) scan. 
b)
Congestive cardiac failure of ≥Grade 3 severity according to New York Heart Association 
(NYHA) functional classification defined as patients with marked limitation of activity and who 
are comfortable only at rest.
c)
Unstable cardiac disease including unstable angina or hypertension as defined by the need for 
overnight hospital admission within the last 3 months (90 days).
d)
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 (AV) 
block, presence of cardiac pacemaker or defibrillator, or other significant arrhythmias. 
e)
Screening 12-lead electrocardiogram (ECG) with measurable QTc interval of ≥470 msec. 
(Fridericia's formula should be used to calculate the QTc interval throughout the study.)
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7.
Known history of human immunodeficiency virus (HIV) infection or seropositive results consistent 
with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) 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:
a)
Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or ocular 
hypertension, uncontrolled diabetes mellitus) or
b)
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.
Study Treatment:
In the dose-escalation part of the study (Phase 1 Part A), subjects will receive 1 of up to potentially 2 
ASTX029 dosing regimens (Regimen 1 or Regimen 2). Subjects enrolled in Regimen 1 (continuous 
dosing) will receive ASTX029 orally once a day on Days 1 through 21 of each 21-day cycle. If Regimen 
2 (intermittent dosing) is opened to enrollment, subjects enrolled in Regimen 2 will receive ASTX029 
orally once a day on Days 1 through 14 of each 21-day cycle. Initially, subjects will be allocated to 
Regimen 1 (continuous dosing). Subjects in the first cohort of Regimen 1 will receive a flat starting dose 
of 10 mg QD. Dose levels for subsequent cohorts will be determined by the DSRC. Planned initial 
escalation will be 100% (doubling the dose) until 160 mg. Smaller increments of dose escalation will be 
used above 160 mg. Dose doubling will also be discontinued if any 1 of the following occurs within a 
cohort:

1 subject experiences a DLT.

Any study-drug-related clinically significant ≥Grade 2 AE not adequately managed or resolved to 
baseline or Grade 1 by supportive treatment that, per the DSRC, indicates further dose doubling 
would be potentially unsafe for future subjects.

Any study-drug-related AE or confluence of AEs that, per the DSRC, indicates further dose 
doubling would be potentially unsafe for future subjects.
Dose escalation will then proceed in smaller increments (eg, by a 50% increase initially and an ~25% 
increase at the higher dose levels over the previous level) after review of safety and PK data from 
Cycle 1 in at least 3 subjects and recommendations from the DSRC. Also, after this point, the sponsor, 
with approval of the DSRC, will determine if Regimen 2 is to be opened for enrollment. 
At any point after Cycle 1, the dose level may be reduced for individual subjects in the event of 
unacceptable treatment-related toxicity. One or more dose levels (and regimens) may be studied in 
Phase 1 Part B to supplement available safety, PK, and/or clinical activity data and to evaluate target 
engagement in fresh tumor tissue biopsies.
The dose level and dosing regimen used in Phase 2 will be determined by the results of Parts A and B of 
the Phase 1 portion of the study.
Study Endpoints:
Primary Endpoints

Phase 1: Incidences of DLTs and AEs to determine the MTD of up to 2 dosing regimens of 
ASTX029 and the RP2D and regimen to be taken to Phase 2.

Phase 2: Clinical activity assessed by ORR according to RECIST v1.1 criteria.
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Secondary Endpoints

PK parameters of ASTX029, including area under the curve (AUC), maximum concentration (Cmax), 
minimum concentration (Cmin), time to reach maximum concentration (Tmax), elimination half-life 
(t½), food effect on ASTX029 PK parameters, and other secondary PK parameters of ASTX029 if 
data permit; analysis of ASTX029 metabolites if applicable.

Inhibition of pRSK protein in response to ASTX029 treatment in tumor biopsies.

PFS.

OS.

DCR.

DOR.
Exploratory Endpoints

Suppression of mutant clones in circulating tumor DNA (ctDNA).

Explore additional biomarkers of ASTX029 activity.
Study Assessments and Procedures:
Efficacy Assessments: 
The ORR, PFS, and DOR endpoints will be based on the investigator’s assessment of target and 
non-target lesions according to RECIST v1.1; computed tomography (CT) or magnetic resonance 
imaging (MRI) scans (or other appropriate disease evaluation method, including tumor marker 
measurement, as applicable) will be performed at baseline and every 2 cycles for the first 4 cycles, and 
then every 4 cycles (±1 cycle) thereafter until clinical and/or radiographic disease progression, death, or 
the subject withdraws consent. Subjects will be followed for OS.
Pharmacokinetics Assessments: 
Serial blood sampling (up to 24 hours postdose) on the following study days will allow assessment of 
systemic exposures of ASTX029:

Phase 1: Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 2 Day 1 (C2D1), and Cycle 2 Day 2 
(C2D2) for Regimen 1 and C1D1, C1D2, Cycle 1 Day 14 (C1D14), and Cycle 1 Day 15 (C1D15) 
for Regimen 2. 

Phase 2: C1D1, C1D2, C2D1, and Cycle 3 Day 1 (C3D1) for Regimen 1 and C1D1, C1D2, C1D14, 
C1D15, and C3D1 for Regimen 2. 
At specified study visits, blood samples, including predose and trough samples, will be collected. 
Additional ad hoc blood sample(s) may be collected per investigator discretion, for PK measurement at 
any time, including after the last dose, if there is a suspected safety issue. Plasma drug concentration 
data will be used to determine the PK parameters listed under Secondary Endpoints in all subjects 
during Cycle 1 and Cycle 2 if data are evaluable.
Pharmacodynamic and Biomarker Assessments:
The pharmacodynamic modulation and target engagement will be explored in fresh tumor tissue 
biopsies (when available). Identification and monitoring of potential biomarkers (DNA, RNA, and 
protein) of ASTX029 activity will be assessed in ctDNA, blood, and tumor tissue biopsies. 
Safety Assessments:
At each study visit, safety will be monitored by recording AEs, serious adverse events (SAEs), DLTs, 
and concomitant medications; additional safety assessments at selected visits include complete or 
symptom-directed physical examinations (PEs), weight and height, vital signs, Eastern Cooperative 
Oncology Group (ECOG) performance status, 12-lead ECGs, ECHO/MUGA scans, and clinical 
laboratory tests (hematology, coagulation, serum chemistry, and urinalysis). All AEs will be graded by 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
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Sample Size and Statistical Analyses:
Sample Size Calculation:
The dose-escalation part of the study (Phase 1 Part A) follows a 3+3 study design, with a cohort size of 
either 3 or 6 evaluable subjects. Dose escalation will continue until an MTD is determined for each 
dosing regimen evaluated.
For Phase 1 Part B, a sample size of 14 evaluable subjects will ensure a 90% probability of observing at 
least 1 adverse reaction to treatment for any adverse reaction with a ≥15% incidence. Evaluable subjects 
for Part B are all subjects who receive any amount of study drug.
For Phase 2, the sample size is based on a Simon’s Optimal 2-stage design. Each cohort will enroll 
10 subjects into the first stage. Should ≥2 first-stage subjects respond, an additional 19 subjects will be 
enrolled into the second stage. Therefore, up to 29 subjects will be used for each treatment cohort. The 
sample size, (10+19) 29, under this Simon’s Optimal 2-stage design, will achieve a power of 80% to test 
the null hypothesis of ORRp0 ≤0.1 at a 1-sided alpha of 0.05 assuming the response rate p1 is 0.3. For 
Stage 2, the null hypothesis will be rejected if ≥6 responses are observed in a cohort of 29 subjects. For 
Phase 2 Cohort F (which will enroll patients with various tumor types and gene aberrations), the 
sponsor, with approval of the DSRC, may expand enrollment for a particular molecularly defined 
subpopulation in which the most number of responses are observed to 10 or 29 subjects under the same 
Simon’s Optimal 2-stage design as for the other cohorts for better assessment of activity in that disease 
subgroup (Optional Cohort F Expansion). It is expected that no more than 2 subgroups will be expanded 
in this manner.
Efficacy: 
Efficacy analysis (ORR) will be conducted on all subjects who had disease assessment at baseline and 
who received study treatment and had at least 1 follow up disease assessment visit or subjects who died 
or stopped treatment before the first scheduled disease assessment due to clinical progression or toxicity. 
Objective response (complete response [CR] + partial response [PR]) rate will be calculated, and its 
90% Clopper-Pearson exact confidence interval (CI) will be provided. Disease control (CR + PR + 
stable disease [SD]) rate will be analyzed similarly. Subjects who receive any amount of study treatment 
will be included for PFS and OS analyses using the Kaplan-Meier procedure. Estimates and the 90% CIs 
for the median PFS and OS will also be provided. The DOR will be summarized with descriptive 
statistics, including arithmetic mean, standard deviation, median, and range, for subjects who have 
overall responses.
Pharmacokinetics/Pharmacodynamics:
The PK parameters for ASTX029 will be derived for each subject using a non-compartmental approach 
and will be summarized using descriptive statistics, including mean, standard deviation, median, and 
range. Values at baseline and changes from baseline (if appropriate) of the pharmacodynamic 
parameters and biomarkers assessed will be summarized descriptively using mean, standard deviation, 
median, minimum, and maximum for continuous variables and counts and percentages for categorical 
variables.
Safety:
Safety analyses will be performed on all subjects who receive any amount of study treatment (Safety 
Analysis Set). Safety will be assessed by subject-reported and investigator-observed AEs, along with 
concomitant medications, PEs, clinical laboratory tests (hematology, coagulation, serum chemistry, and 
urinalysis), vital signs, ECOG performance status, ECGs, and ECHO/MUGA scans. All AEs will be 
graded according to the NCI CTCAE, v4.03. Treatment exposure, AEs (including relatedness and 
severity), SAEs, reasons for treatment discontinuation, will be tabulated. Concomitant medication will 
be coded using the World Health Organization (WHO) Drug Dictionary. The number and proportion of 
subjects who have DLTs will be summarized by cohort and regimen in Phase 1 Part A. No interim 
analysis is planned.
Study Duration and Termination:
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The expected study duration is approximately 5 years (61 months), including approximately 55 months 
for recruitment and approximately 6 months for safety follow-up. 
The Sponsor may stop the study at any time. In case of this event, the Sponsor will make reasonable 
efforts to ensure subjects are transitioned off study in an orderly manner. Reasons for early termination 
include, but are not limited to, lack of preliminary clinical activity or safety concerns.
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TABLE OF CONTENTS
SUMMARY OF CHANGES...........................................................................................................2
PROTOCOL SYNOPSIS ................................................................................................................4
ABBREVIATIONS AND DEFINITIONS....................................................................................19
1.
INTRODUCTION AND BACKGROUND ...............................................................22
1.1.
Background of the Disease.........................................................................................22
1.2.
Background of Treatment Options .............................................................................22
1.2.1.
Mechanism of Action of ERK Inhibitors....................................................................22
1.2.2.
ERK Inhibition as Potential Antitumor Treatment Option.........................................24
1.3.
Summary of Nonclinical and Clinical Data for ASTX029.........................................25
1.3.1.
Toxicology in rat and dog studies (single-dose and repeat-dose studies) 
(Section 1.3.2.4)..........................................................................................................25
1.3.1.1.
Chemical Name of Compound ...................................................................................25
1.3.2.
Nonclinical Data.........................................................................................................26
1.3.2.1.
Absorption, Distribution, Metabolism, and Excretion Studies and 
Nonclinical Pharmacokinetics ....................................................................................26
1.3.2.2.
Nonclinical Pharmacology Studies.............................................................................27
1.3.2.3.
Safety Pharmacology..................................................................................................27
1.3.2.4.
Toxicology Studies.....................................................................................................28
1.3.3.
Clinical Data and Human Pharmacokinetics..............................................................32
1.4.
Summary of Data for Other Study Treatment ............................................................32
1.5.
Potential Risks and Benefits to Human Subjects........................................................32
2.
RATIONALE .............................................................................................................34
2.1.
Rationale for the Study...............................................................................................34
2.2.
Rationale for ASTX029 Dose and Regimen and Justification of the Starting 
Dose............................................................................................................................34
3.
STUDY OBJECTIVES ..............................................................................................36
3.1.
Primary Objectives .....................................................................................................36
3.2.
Secondary Objectives .................................................................................................36
3.3.
Exploratory Objectives...............................................................................................36
4.
INVESTIGATIONAL PLAN.....................................................................................37
4.1.
Overall Study Design..................................................................................................37
4.1.1.
Phase 1........................................................................................................................39
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4.1.2.
Phase 2........................................................................................................................40
4.2.
Discussion of Study Design........................................................................................42
4.3.
Study Endpoints..........................................................................................................43
4.3.1.
Primary Endpoints ......................................................................................................43
4.3.2.
Secondary Endpoint(s)................................................................................................43
4.3.3.
Exploratory Endpoint(s) .............................................................................................43
4.4.
Data and Safety Review Committee...........................................................................43
5.
SELECTION AND WITHDRAWAL OF SUBJECTS..............................................45
5.1.
Number of Subjects and Centers ................................................................................45
5.2.
Inclusion Criteria ........................................................................................................45
5.3.
Exclusion Criteria.......................................................................................................46
5.4.
Treatment Discontinuation and Withdrawal of Subjects............................................48
5.4.1.
Discontinuation From Study Treatment .....................................................................48
5.4.2.
Withdrawal From the Study........................................................................................49
5.4.3.
Replacement of Subjects.............................................................................................49
5.4.4.
End of Study ...............................................................................................................49
5.4.5.
Study Extension..........................................................................................................49
6.
ENROLLMENT AND RANDOMIZATION PROCEDURES..................................51
6.1.
Randomization............................................................................................................51
7.
STUDY TREATMENTS............................................................................................52
7.1.
Investigational Medicinal Product (ASTX029)..........................................................52
7.1.1.
Drug Substance, Drug Product, and Packaging..........................................................52
7.1.2.
Storage........................................................................................................................52
7.1.3.
ASTX029 Reconstitution............................................................................................53
7.1.4.
ASTX029 Regimens and Dose Levels .......................................................................53
7.1.5.
ASTX029 Administration...........................................................................................55
7.1.6.
Transition From Powder-in-Bottle Dosage Form to Tablet Dosage Form.................56
7.1.7.
Transition From Fed to Fasted Administration ..........................................................57
7.2.
Active Comparator or Placebo....................................................................................57
7.3.
Dose-Escalation Guidelines and Recommended Phase 2 Dose Decision ..................57
7.4.
Definition of Dose-Limiting Toxicities......................................................................58
7.5.
Guidelines for Adjusting, Withholding, or Discontinuing Study Treatment..............59
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7.6.
Concomitant Treatment ..............................................................................................60
7.6.1.
Supportive, Prophylactic, or Other Treatments..........................................................60
7.6.2.
Prohibited Medications and Substances .....................................................................60
7.7.
Overdose Instructions.................................................................................................61
8.
RISKS/PRECAUTIONS ............................................................................................63
9.
STUDY ASSESSMENTS AND PROCEDURES......................................................64
9.1.
Preliminary Clinical Activity Assessments ................................................................64
9.2.
Pharmacokinetic/Pharmacodynamic/Biomarker Assessments...................................64
9.2.1.
Pharmacokinetic Assessments....................................................................................64
9.2.2.
Pharmacodynamic and Biomarker Assessments ........................................................66
9.2.3.
Total Volume of Blood Samples to Be Drawn...........................................................68
9.3.
Safety Assessments.....................................................................................................68
9.3.1.
Adverse Events...........................................................................................................68
9.4.
Study Procedures ........................................................................................................68
9.4.1.
Physical Examination .................................................................................................68
9.4.2.
Vital Signs ..................................................................................................................69
9.4.3.
ECOG Performance Status .........................................................................................69
9.4.4.
12-Lead ECG..............................................................................................................69
9.4.5.
ECHO or MUGA Scan...............................................................................................70
9.4.6.
Ophthalmic Examination............................................................................................70
9.4.7.
Clinical Laboratory Tests ...........................................................................................70
9.4.8.
Disease Assessments ..................................................................................................71
9.4.9.
Schedules of Events....................................................................................................71
9.4.10.
Screening and Baseline Procedures............................................................................81
9.4.11.
Treatment and Follow-up Procedures.........................................................................82
9.4.11.1.
Cycle 1 – Week 1........................................................................................................82
9.4.11.2.
Cycle 1 – Week 2 – Day 8..........................................................................................83
9.4.11.3.
Cycle 1 – Week 2 – Day 14 Regimen 2 Only.............................................................84
9.4.11.4.
Cycle 1 – Week 3 – Day 15........................................................................................85
9.4.11.5.
Cycle 2 – Week 1........................................................................................................85
9.4.11.6.
Cycle 2 – Week 2 – Day 8..........................................................................................87
9.4.11.7.
Cycle 2 – Week 3 – Day 15........................................................................................88
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9.4.11.8.
Cycle 2 End of Cycle (before Cycle 3 Day 1)............................................................88
9.4.11.9.
Cycles 3 Through 6 – Week 1 – Day 1.......................................................................88
9.4.11.10.
Cycles 3 Through 6 – Week 2 – Day 8.......................................................................89
9.4.11.11.
Cycle 3 Through 6 – Week 3 – Day 15 ......................................................................90
9.4.11.12.
End of Cycle 4 and at End of Every 4 Cycles (±1 Cycle) After Cycle 4 
(Before Day 1 of Cycle 5 and Before Day 1 of Every 4 Cycles [±1 Cycle] 
After Cycle 5) .............................................................................................................90
9.4.12.
Cycle 7 and Subsequent Cycles..................................................................................90
9.4.13.
Treatment Termination Visit ......................................................................................90
9.4.14.
30-day Safety Follow-up Visit....................................................................................91
9.4.15.
Long-Term Follow-up of Health Status .....................................................................91
9.5.
Missed Evaluations.....................................................................................................91
10.
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS.....................................................................................................................92
10.1.
Definitions ..................................................................................................................92
10.1.1.
Adverse Event (AE)....................................................................................................92
10.1.2.
Serious Adverse Events (SAEs) .................................................................................92
10.2.
Adverse Event Reporting and Descriptions................................................................93
10.2.1.
Severity.......................................................................................................................93
10.2.2.
Relationship to Study Treatment (Suspected Adverse Reactions) .............................94
10.2.3.
Reporting Requirements for Pregnancy and Abortion ...............................................95
10.2.4.
Reporting Requirements for Serious Adverse Events (SAEs) ...................................95
10.3.
Follow-up for Adverse Events....................................................................................96
11.
STATISTICS..............................................................................................................97
11.1.
Sample Size ................................................................................................................97
11.2.
Analysis Sets to Be Analyzed.....................................................................................97
11.2.1.
All Subject Analysis Set.............................................................................................97
11.2.2.
Efficacy Analysis Set..................................................................................................98
11.2.3.
Safety Analysis Set.....................................................................................................98
11.2.4.
PK Analysis Set..........................................................................................................98
11.2.5.
Pharmacodynamic and Biomarker Analysis Set.........................................................98
11.3.
Schedule of Analyses..................................................................................................98
11.4.
Disposition..................................................................................................................98
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11.5.
Analysis of Demographic and Baseline Data.............................................................98
11.6.
Efficacy Analyses.......................................................................................................99
11.6.1.
Objective Response and Disease Control Rate...........................................................99
11.6.2.
Progression-free Survival ...........................................................................................99
11.6.3.
Overall Survival..........................................................................................................99
11.6.4.
Duration of Response .................................................................................................99
11.7.
Safety Analyses ..........................................................................................................99
11.8.
Pharmacokinetic Analyses........................................................................................100
11.9.
Pharmacodynamic/Biomarker Analyses...................................................................100
11.10.
Interim Analysis........................................................................................................101
11.11.
Procedures for Handling Missing, Unused, and Spurious Data ...............................101
12.
STUDY DURATION AND TERMINATION.........................................................102
13.
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS...........................103
13.1.
Compliance Statement..............................................................................................103
13.2.
Informed Consent .....................................................................................................103
13.3.
Institutional Review Board or Independent Ethics Committee (IRB/IEC) ..............103
14.
ADMINISTRATIVE PROCEDURES.....................................................................104
14.1.
Sponsor Responsibilities...........................................................................................104
14.1.1.
Study Supplies ..........................................................................................................104
14.1.2.
Investigator Training ................................................................................................104
14.1.3.
Ongoing Communication of Safety Information During the Study .........................104
14.1.4.
Study Monitoring......................................................................................................105
14.1.5.
Study Auditing and Inspecting .................................................................................105
14.2.
Investigator Responsibilities.....................................................................................105
14.2.1.
Subject Screening Log..............................................................................................105
14.2.2.
ASTX029 and VFR Accountability..........................................................................105
14.2.3.
Reporting and Recording of Study Data...................................................................106
14.2.4.
Source Documentation..............................................................................................106
14.2.5.
Tissue and Blood Sample Collection/Storage ..........................................................107
14.2.6.
Records Retention.....................................................................................................107
14.3.
Clinical Trial Insurance ............................................................................................108
14.4.
Study Administrative Letters and Protocol Amendments ........................................108
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15.
POLICY FOR PUBLICATION AND PRESENTATION OF DATA.....................109
16.
REFERENCES .........................................................................................................110
17.
APPENDICES..........................................................................................................115
APPENDIX 1.
ECOG PERFORMANCE STATUS ................................................................116
APPENDIX 2.
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS ...................................................................117
APPENDIX 3.
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS, 
VERSION 1.1...........................................................................................................118
APPENDIX 4.
MANAGEMENT OF SKIN TOXICITIES .....................................................125
APPENDIX 5.
MANAGEMENT OF VISUAL CHANGES ...................................................127
APPENDIX 6.
MANAGEMENT OF DIARRHEA.................................................................128
APPENDIX 7.
LIVER STATUS MONITORING AND MANAGEMENT OF 
POTENTIAL LIVER INJURY ................................................................................129
APPENDIX 8.
DOSE MODIFICATION FOR DECREASE IN LEFT 
VENTRICULAR EJECTION FRACTION .............................................................131
APPENDIX 9.
MODIFICATIONS DURING THE COVID-19 HEALTH 
EMERGENCY .........................................................................................................132
LIST OF TABLES
Table 1:
Proposed Human Starting Dose..................................................................................34
Table 2:
Gene Aberrations Selected for Inclusion in Cohort F ................................................41
Table 3:
Example of Possible ASTX029 Dose Levels in Part A..............................................54
Table 4:
Phase 1: Plasma Collection Schedule for Pharmacokinetic Analysis 
(Regimen 1) ................................................................................................................64
Table 5:
Phase 1: Plasma Collection Schedule for Pharmacokinetic Analysis 
(Regimen 2) ................................................................................................................65
Table 6:
Phase 2: Plasma Collection Schedule for Pharmacokinetic Analysis 
(Regimen 1) ................................................................................................................65
Table 7:
Phase 2: Plasma Collection Schedule for Pharmacokinetic Analysis 
(Regimen 2) ................................................................................................................66
Table 8:
Sample Collection Schedule for Biomarker Analyses................................................67
Table 9:
Tumor Tissue Collection Schedule for Biomarker Analyses .....................................67
Table 10:
Clinical Laboratory Tests ...........................................................................................70
Table 11:
Schedule of Events Regimen 1 – Continuous (Days 1 Through 21) Dosing .............72
Table 12:
Schedule of Events Regimen 2 – Intermittent (Days 1 Through 14) Dosing.............75
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Table 13
Schedule of Events – Study Extension Phase.............................................................79
Table 14:
Overall Response......................................................................................................123
Table 15:
Suggested Management and Dose Modification Guidelines for Skin 
Toxicities ..................................................................................................................125
Table 16:
Suggested Management and Dose Modification for Visual Changes ......................127
Table 17:
Suggested Management and Dose Modification for Diarrhea .................................128
Table 18:
Suggested Action and Dose Modification for LVEF Decrease................................131
LIST OF FIGURES
Figure 1:
The MAPK Signaling Pathway ..................................................................................24
Figure 2:
Study Schema .............................................................................................................38
Figure 3:
ASTX029-01 Phase 1 Part A Dose Escalation Flowchart..........................................54
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ABBREVIATIONS AND DEFINITIONS
%CV
percent coefficient of variation
ADL
activities of daily living
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AKT
protein kinase B 
ALP
alkaline phosphatase
ALT
alanine aminotransferase (serum glutamic pyruvic transaminase [SGPT])
ARAF
A isoform of RAF
AST
aspartate aminotransferase (serum glutamic oxaloacetic transaminase [SGOT])
ATC
Anatomical Therapeutic Chemical
AUC
area under the curve
AUC0-inf
area under concentration-time curve from time 0 to infinity
AUC0-t
area under the plasma concentration-time curve from the start of dosing (0) to the last 
quantifiable time point (t) 
AUClast
area under concentration-time curve from time 0 to the last data point
AV
atrioventricular
BID
twice a day
BRAF
B isoform of RAF kinase
BRAT
bananas, rice, applesauce, toast
BSA
body surface area
BSEP
bile salt export pump
CCND1
cyclin D1
ctDNA
circulating tumor DNA
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum concentration
Cmin
minimum concentration
CRAF
C isoform of RAF
CR
complete response
CRC
colorectal cancer
CRO
contract research organization
CSR
central serous retinopathy
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CxDx
Cycle x Day x
CYP3A
cytochrome P450, family 3, subfamily A
DCR
disease control rate
DDI
drug-drug interactions
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOS
duration of response
DRF
dose-range finding
DSRC
Data and Safety Review Committee
DUSP
dual specificity phosphatase
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
EMEA
European Agency for the Evaluation of Medicinal Products
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ERK
extracellular signal-regulated kinase
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin embedded
FIH
first-in-human
FU
follow-up
g-tube
gastrostomy tube
GCP
Good Clinical Practice
GI
gastrointestinal
GLP
Good Laboratory Practice
GNA11
G protein subunit alpha 11
GNAQ
G protein subunit alpha q
GRAS
generally recognized as safe
GRB2
growth factor receptor-bound protein 2
GTPase
guanosine-5'-triphosphate enzyme
HBV
hepatitis B virus
HCV
hepatitis C virus
HED
human equivalent dose
hERG
human ether-a-go-go-related gene
HIV
human immunodeficiency virus
HNSTD
highest non-severely toxic dose
HRAS
Harvey RAS
IB
Investigator Brochure
IC50
concentration giving half-maximal inhibition
ICF
informed consent form
ICH
International Council for Harmonisation
ID
identification
IEC
Independent Ethics Committee 
IMP
investigational medicinal product (ASTX029 in this protocol)
INR
international normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
IVD
in vitro diagnostic
LLN
lower limit of normal
LVEF
left ventricular ejection fraction
KRAS
Kirsten RAS
m
minute(s)
MAPK
mitogen-activated protein kinase
MedDRA
Medical Dictionary for Regulatory Activities
MEK
mitogen-activated extracellular signal-regulated kinase 
MHRA
Medicines and Healthcare Products Regulatory Agency
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition
NCI
National Cancer Institute
NE
inevaluable
NOAEL
no-observable adverse effect level
NRAS
neuroblastoma RAS
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival
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P
phosphorylated
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PiB
powder in bottle
PR
partial response
pRSK
phosphorylated ribosomal s6 kinase
PT
Preferred Term
PTT
partial thromboplastin time
QD
daily
QT
measure of time between the start of the Q wave and the end of the T wave in the heart’s 
electrical cycle
QTc
QT interval corrected for heart rate
RAF
rapidly accelerated fibrosarcoma
RAS
rat sarcoma virus
RDE
recommended dose for expansion
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
rSDV
remote source data verification
RSK
ribosomal s6 kinase
RTK
receptor tyrosine kinase
RT-PCR
reverse transcription polymerase chain reaction
RVO
retinal vein occlusion
SAE
serious adverse event
SD
stable disease
SDD
spray-dried dispersion
SOC
System Organ Class
SOS
Son of Sevenless
SPRY
sprouty
STD10
severely toxic dose in 10% of the animals
SUSAR
serious unexpected suspected adverse reaction
t1/2
elimination half-life
TEAE
treatment-emergent adverse event
THP
tetrahydropyran
tmax
time to reach maximum concentration
TPGS
d-α-tocopherol polyethylene glycol 1000 succinate
Tx Term
Treatment Termination
ULN
upper limit of normal
US
United States
VFR
vehicle for reconstitution
Vss
volume of distribution at steady state
WHO
World Health Organization
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1.
INTRODUCTION AND BACKGROUND
ASTX029 is a synthetic small molecule inhibitor of extracellular signal-regulated kinases 
(ERKs) 1/2 that has been shown to have potent tumor growth inhibitory activity in nonclinical 
cancer models with oncogenic activation of the Ras-Raf-MEK-ERK signal transduction cascade 
(also referred to as the mitogen-activated protein kinase [MAPK] signal pathway) 
(Section 1.3.2). The main objectives of this Phase 1-2 study are to identify a safe and tolerated 
dose and regimen of ASTX029 and to evaluate preliminary clinical activity of ASTX029 in 
subjects with advanced or refractory solid malignancies who are not candidates for approved or 
available therapies, and for whom standard life-prolonging measures are not available. Initially, 
patients with any type of solid tumor will be eligible for enrollment in this study. In later parts of 
this study, preliminary single-agent antitumor activity of ASTX029 will be assessed in tumors 
characterized by gene aberrations in the MAPK signal pathway that may confer sensitivity to 
ASTX029.
1.1.
Background of the Disease
Approximately 1.69 million new cancer cases and 600,920 cancer deaths are projected to occur 
in the US in 2017 (Siegel et al 2017). Although the combined cancer death rates have been 
continuously declining for 2 decades, the outlook remains bleak for patients with advanced 
malignancies.
1.2.
Background of Treatment Options
Historically, medical approaches to treat advanced malignancies have typically involved surgery, 
radiotherapy, and/or cytotoxic chemotherapy. Advances in genomics and molecular biology have 
led to successful development of therapies targeting specific driver mutations in cancer cells (eg, 
epidermal growth factor receptor [EGFR], B isoform of RAF kinase [BRAF], ALK, BCR-ABL, 
KIT) (Friedman et al 2015; Xu et al 2014). More recently, cancer immunotherapy has also been 
shown to significantly improve the outcomes of many cancers. However, a significant proportion 
of patients eventually relapse due to acquired resistance, and others present intrinsic resistance 
mechanisms (Farkona et al 2016). Thus, there is an unmet need for new approaches to stop the 
uncontrolled growth of cancer cells in patients whose tumors have progressed despite currently 
available treatments (Section 2.1).
1.2.1.
Mechanism of Action of ERK Inhibitors
ERK1/2 are ubiquitously expressed protein serine/threonine kinases that comprise a key 
component of the MAPK signaling pathway) (Figure 1). The MAPK signaling pathway regulates 
a variety of cellular processes including cell cycle progression, cell survival, and proliferation. 
The pathway responds to the extracellular stimulation of cell-surface receptor tyrosine kinases 
(RTKs). Upon activation of RTKs, the rat sarcoma virus (RAS) guanosine-5'-triphosphate 
enzymes (GTPases) (Kirsten RAS [KRAS], neuroblastoma RAS [NRAS], and Harvey RAS 
[HRAS]) are converted from an inactive GDP-bound state to an active GTP-bound state. 
Activated RAS promotes the activation of rapidly accelerated fibrosarcoma (RAF) kinases (A 
isoform of RAF [ARAF], B isoform of RAF [BRAF], and C isoform of RAF [CRAF]), which, in 
turn, phosphorylate and activate the dual-specificity mitogen-activated extracellular signal-
regulated kinases (MEKs) MEK1/2. Subsequently, MEK phosphorylates and activates ERK1/2, 
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which, upon activation, phosphorylate multiple nuclear and cytoplasmic substrates including 
ribosomal S6 kinase (RSK), which promotes cell proliferation and survival, and multiple 
transcription factors that promote cell proliferation and differentiation (Roskoski 2012; Anjum 
and Blenis 2008; Murphy et al 2002; Figure 1). 
ERK is commonly upregulated in cancer, as a result of activating mutations within upstream 
components of the MAPK pathway, such as RAS and RAF. Activating RAS mutations are 
contained in 30% of human cancers (Roberts and Der 2007). KRAS mutations are particularly 
prevalent in pancreatic adenocarcinoma, non-small cell lung cancer (NSCLC), and colorectal 
cancer (CRC) (Neuzillet et al 2014; Prior et al 2012). NRAS and HRAS mutations have high 
prevalence in melanoma and bladder cancer, respectively (Prior et al 2012). BRAFV600E is the 
most common activating BRAF mutation and is found in melanoma, CRC, and NSCLC 
(Neuzillet et al 2014; Wan et al 2004).
Two distinct classes of ERK inhibitor have been described to date (Blake et al 2016; Morris et al 
2013). Both classes directly inhibit the kinase activity of ERK. In addition, the second class also 
prevents the phosphorylation of ERK itself. Two examples of the first class of ERK inhibitor 
(which solely inhibit the phosphorylation of downstream ERK substrates) have been tested 
clinically and have shown some preliminary clinical activity in MAPK-activated cancers; namely 
ulixertinib (BVD-523) and GDC-0994 (Sullivan et al 2018; Li et al presentation 2017; Varga et 
al 2020; Infante et al abstract 2015; Infante et al presentation 2015). SCH772984 is an example 
of the second class of ERK inhibitor, which, in addition to inhibiting ERK kinase activity, also 
prevents the phosphorylation of ERK (Morris et al 2013). ASTX029 belongs to this second class 
of ERK inhibitor and is able to modulate the phosphorylation of ERK as well as directly inhibit 
kinase activity (as presented in the current ASTX029 Investigator Brochure [IB] Section 4.1.1.3). 
An ERK inhibitor with this profile (dual mechanism of MAPK pathway inhibition) may prove to 
be more efficacious than the first class of ERK inhibitor in tumors driven by this pathway, which 
provides the rationale for clinically testing ASTX029 in this study.
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Figure 1:
The MAPK Signaling Pathway
AKT=protein kinase B; CCND1=cyclin D1; DUSP=dual specificity phosphatase; ERK=extracellular signal-regulated kinase; 
GRB2=growth factor receptor-bound protein 2; MAPK=mitogen-activated protein kinase; MEK=mitogen-activated extracellular 
signal-regulated kinase; P=phosphorylated; RAF=rapidly accelerated fibrosarcoma; RAS=rat sarcoma virus; RSK=ribosomal s6 
kinase; RTK=receptor tyrosine kinase; SOS=Son of Sevenless; SPRY=sprouty. 
Source: Adapted from Lito et al 2013
1.2.2.
ERK Inhibition as Potential Antitumor Treatment Option
Targeting the MAPK pathway has been clinically validated by BRAF inhibitors (eg, 
vemurafenib and dabrafenib) and MEK inhibitors (eg, trametinib and cobimetinib) 
(https://www.accessdata.fda.gov/scripts/cder/daf/). These agents elicit profound antitumor 
responses in BRAFV600E-mutant melanoma patients, although responses are often short-lived, due 
to the onset of acquired drug resistance (Flaherty et al 2012; Hauschild et al 2012; Little et al 
2012; Chapman et al 2011; Solit and Rosen 2011). A common feature of RAF or MEK inhibitor 
resistance mechanisms is the reactivation of ERK signaling, which drives proliferation and 
survival of the cells, even in the presence of BRAF and MEK inhibitors (Little et al 2012; Wagle 
et al 2011; Nazarian et al 2010; Emery et al 2009). 
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As ERK is the primary downstream effector of the MAPK pathway, it is hypothesized that ERK 
inhibitors may prove to be less susceptible to oncogenic bypass than RAF and MEK inhibitors 
and, therefore, have the potential to improve clinical outcomes in these patient populations 
(Nissan et al 2013).
Several ERK inhibitors have recently entered clinical development, although none have gained 
regulatory approval yet. ERK inhibitors in clinical development include GDC-0994 (Genentech; 
oral route), ulixertinib (BioMed Valley; oral route), LY3214996 (Eli Lilly; oral route) CC-90003 
(Celgene; oral route) LTT462 (Novartis; oral route), KO-947 (Kura Oncology; intravenous [IV] 
route) and MK-8353 (Merck Sharp & Dohme Corp; oral route) (https://clinicaltrials.gov/). 
Notably, in the Phase 1 study of GDC-0994 (an ERK1/2 inhibitor), partial responses were 
observed in 2 subjects with BRAF mutant CRC (Varga et al 2020). Responses were also 
observed in subjects with BRAF and NRAS mutations enrolled in a Phase 1-2 study of 
ulixertinib (Sullivan et al 2018; Li et al presentation 2017; Infante et al abstract 2015; Infante et 
al presentation 2015). 
ASTX029 is a synthetic small molecule that was developed using fragment-based drug discovery 
platform. Unlike most ERK inhibitors currently in the clinic, ASTX029 both prevents the 
phosphorylation of ERK and directly inhibits ERK kinase activity, which is expected to produce 
a more effective blocking of the MAPK pathway. Please refer to the current ASTX029 IB 
Section 4.1. 
1.3.
Summary of Nonclinical and Clinical Data for ASTX029
The following nonclinical data are summarized in this section. Please refer to the current 
ASTX029 IB for complete information.

Absorption, distribution, metabolism, and excretion (ADME) properties in mouse, rat, 
dog, non-human primate, and human studies (Section 1.3.2.1).

Pharmacokinetic (PK) properties in mouse, rat, and dog studies (Section 1.3.2.1).

Nonclinical pharmacology properties of ASTX029 (Section 1.3.2.2).

In vitro safety pharmacology studies and in vivo cardiovascular safety pharmacology 
of ASTX029 in dogs (Section 1.3.2.3).
1.3.1.
Toxicology in rat and dog studies (single-dose and repeat-dose studies) 
(Section 1.3.2.4).
1.3.1.1.
Chemical Name of Compound
Refer to Section 7.1.1 for the molecular formula of ASTX029.
The oral and IV routes of administration were used in the animal studies. Oral administration is 
proposed for this FIH study.
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1.3.2.
Nonclinical Data
1.3.2.1.
Absorption, Distribution, Metabolism, and Excretion Studies and Nonclinical 
Pharmacokinetics
ASTX029 in vitro ADME properties were evaluated in mouse, rat, dog, non-human primate, and 
human studies, and in vivo PK properties were evaluated in mouse, rat, and dog studies. 
ASTX029 was moderately permeable in Caco-2 cell monolayer model and displayed efflux that 
was not inhibited with a p-glycoprotein inhibitor. ASTX029 showed very high plasma protein 
binding across species (≥99.4%) and was highly bound to human serum albumin (≥98.5%). 
However, ASTX029 did not appear to bind to human red blood cells. Intrinsic clearance of 
ASTX029 in hepatic microsomes was low (dog) to moderate (mouse, rat, and human) across 
species, but was high in the non-human primate. In hepatic microsomes, 4 metabolites of 
ASTX029 were detected across the 5 species. ASTX029 underwent oxidation of the 
tetrahydropyran (THP) ring and O-demethylation of the methoxyphenyl group to the O-
desmethyl metabolite (AT37200). The O-desmethyl metabolite was detectable in all species. The 
in vivo metabolite profile in the rat was similar to that defined in vitro.
ASTX029 was a CYP3A4 substrate in expressed human CYPs and human liver microsomes 
demonstrating concentration dependent clearance in both test systems. The inhibition of the 
metabolism of ASTX029 by ketoconazole supported the conclusion that metabolic clearance was 
principally CPY3A4 mediated. In human liver microsomes, ASTX029 was a weak to moderate 
inhibitor of CYP3A4 metabolism, which was substrate dependent. The inhibition of CYP3A4 
increased after a pre-incubation step, indicating time-dependent inhibition of CYP3A4. Weak 
inhibition of CYP2C9 and CYP2C19 by ASTX029 was also observed in human liver 
microsomes.
In a preliminary assessment of transporter interactions, ASTX029 showed moderate inhibition of 
probe substrate uptake by OATP1B1 and weak inhibitory action on uptake of a bile salt export 
pump (BSEP) substrate.
ASTX029 administered via the IV route in mouse, rat, and dog exhibited a low clearance of 
≤25% of liver blood flow across species, with the dog showing the lowest clearance. The volume 
of distribution at steady state (Vss) was low for all species, which is consistent with the very high 
plasma protein binding observed across species. ASTX029 had a short half-life in all species 
following IV administration. Following oral administration, ASTX029 was bioavailable in all 
species with the highest bioavailability being achieved in the dog. There was evidence of pre-
systemic metabolism and low bioavailability in rats at a dose of 1 mg/kg. Separate studies 
showed there was a supra-proportional relationship between dose and exposure in rats at oral 
doses of 1 mg/kg and 100 mg/kg. Evaluation of the elimination routes of ASTX029 in the rat 
showed that 10% of an IV dose was excreted in the bile, with minimal renal elimination. These 
results indicate that the primary mechanism of clearance is likely via metabolism. 
In general, dose proportional PK were observed in mice for oral doses between 50 and 
150 mg/kg. Furthermore, the PK showed no accumulation on repeat administration. 
ASTX029 distributed into tumor xenografts with a plasma to tumor ratio of 0.3 to 0.5. The 
higher plasma concentrations compared to tumor concentrations are likely due to very high 
plasma protein binding of ASTX029. Evaluation of ASTX029 in multiple studies where 
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75 mg/kg was administered orally to male Balb/c nude mice bearing xenografts, indicated the PK 
of ASTX029 were variable.
Determination of the plasma concentrations in dogs following oral administration of ASTX029 
in formulations consisting of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), 
ethanol, and propylene glycol in different ratios showed that the presence of TPGS was 
important for achieving good exposure. The optimal formulation for maximum exposure was 
determined to be 80% propylene glycol, 10% ethanol, and 10% TPGS.
The ASTX029 spray-dried dispersion (SDD)-based tablet (“tablet”) formulation, the SDD 
formulation (suspension), and the powder-in-bottle (PiB) formulation were administered to 
cynomolgus monkeys at a single dose of 20 mg/kg to compare the overall systemic exposures. 
Systemic exposures, as measured by mean area under concentration-time curve from time 0 to 
the last data point (AUClast), were comparable between the tablet and the SDD suspension, 
whereas exposure was 2-fold higher following tablet administration compared to following PiB 
administration, although variability was also higher for SDD-based forms. Please refer to the 
current ASTX029 IB for more information.
Food-effect studies were recently conducted in monkeys and dogs following a single dose of 
ASTX029 tablets at 10 mg/kg or 2 mg/kg, respectively. In 2 monkey studies, animals were dosed 
after having been fed 30 minutes previously or after having been fasted overnight. In a dog 
study, animals were dosed after having been fed a high-fat diet 30 minutes previously or after 
having been fasted overnight. Data from these food-effect studies demonstrate increased 
ASTX029 exposures in monkeys (~3.8- to ~4.3-fold) and dogs (~5.6-fold) following fasted-state 
dosing compared to fed-state dosing. Based on these findings, food may have a negative effect 
on the exposure of ASTX029 in humans.
1.3.2.2.
Nonclinical Pharmacology Studies
In vitro studies with ASTX029 have shown that the compound inhibits ERK2 and ERK1 
catalytic kinase activity with nanomolar potency (2.7 nM and ~3 nM, respectively). The 
inhibition of ERK kinase activity has been demonstrated in cancer cells and in vivo models by 
measuring the effect of ASTX029 on the phosphorylation levels of the ERK substrate RSK. 
Furthermore, experiments with isolated enzymes and cell-based assays confirmed that ASTX029 
prevents the phosphorylation of ERK by MEK without directly inhibiting MEK activity.
Cellular studies have shown that ASTX029 inhibits proliferation in a wide variety of 
MAPK-activated tumor cell lines derived from multiple tumor types. In vivo, oral administration 
of ASTX029, over a range of doses, confers antitumor activity in a number of tumor cell line 
xenograft models with MAPK pathway activation (BRAF-mutant melanoma and CRC, 
KRAS-mutant lung cancer and CRC, and NRAS-mutant melanoma); tumor regression was 
achieved in several of these models. Please refer to the ASTX029 IB for a more detailed 
description.
1.3.2.3.
Safety Pharmacology
ASTX029 was tested for inhibition of the hERG (human ether-a-go-go-related gene) ion channel 
using an automated patch clamp and a manual patch clamp assay and was shown to inhibit hERG 
channel with a half-maximal inhibition (IC50) concentration of 11 µM. As ASTX029 is highly 
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protein bound (greater than 99%), the free fraction or circulating ASTX029 in vivo is unlikely to 
approach these levels. No QT interval corrected for heart rate (QTc) prolongation was observed in 
the Good Laboratory Practice (GLP) in vivo acute cardiovascular safety pharmacology study in 
dogs, in which ASTX029 was administered to telemetered dogs at doses up to 30 mg/kg. No 
relevant effects were noted on arterial blood pressure, heart rate, core body temperature, or lead 
II electrocardiogram (ECG) intervals at any dose level. A higher incidence of second degree 
atrioventricular (AV) block was noted in 1 animal after a 30 mg/kg dose. This may have been 
due to a higher background incidence of arrhythmia in this animal compared to the other animals 
in the study, but this could not be confirmed as this dog did not receive vehicle control or any 
lower doses. Therefore, an association with ASTX029 cannot be completely ruled out at this 
time.
1.3.2.4.
Toxicology Studies
The initiation of the FIH study of ASTX029 (also known as AT35029) is supported by 2 pivotal 
GLP toxicology studies. ASTX029 refers to any form of AT35029, AT35029X refers to the free 
base form, and AT35029W is the monohydrate. These studies used oral twice a day (BID) and 
daily (QD) dosing with ASTX029 for 28 days (followed by a 2-week recovery) in rats and dogs 
and are intended to support the initial clinical regimen to be investigated in late-stage cancer 
patients. Earlier, non-GLP, studies in both species were conducted to enable the design for the 
pivotal GLP studies. The toxicology program for ASTX029 followed ICH and FDA Guidance S9 
Nonclinical Evaluation for Anticancer Pharmaceuticals, dated March 2010 (FDA S9 2010), ICH 
and FDA Guidance M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization for Pharmaceuticals, dated January 2010 (FDA M3(R2) 2010), and 
FDA Guidance Nonclinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals Questions and Answers (R2), dated March 2013 
(FDA 2013).
As the intended initial clinical population consists of patients with advanced cancer, in 
accordance with the ICH Tripartite S9 guidance (FDA S9 2010), certain toxicology studies, such 
as stand-alone neurobehavioral, respiratory safety pharmacology, and genotoxicity studies with 
ASTX029 have not yet been conducted. A GLP cardiovascular safety pharmacology study in 
dogs has been completed and is included in the Safety Pharmacology section above 
(Section 1.3.2.3).
In rats, repeat-dose toxicity of ASTX029 was evaluated first in 3 dose-range finding (DRF) 
studies of 14-days duration using BID and QD dosing, followed by a pivotal 28-day GLP study 
with continuous QD dosing for 28 days (followed by a 2-week recovery period). In the initial 
BID DRF study in male rats, doses above 60 mg/kg/day (30 mg/kg BID) were not tolerated, 
leading to severe body weight loss and early termination. Subsequent studies were conducted 
using QD dosing, based on efficacy data indicating that QD dosing is adequate. The DRF studies 
using either BID or QD dosing consistently showed that dose levels above 60 mg/kg/day were 
not tolerated in either male or female rats. Key findings across all DRF studies were reproducible 
and were consistent with the known class effects of inhibitors of the MAPK pathway (Diaz et al 
2012; Yanochko et al 2013). Changes in hematology (indicative of anemia and/or inflammation) 
and clinical chemistry parameters (indicating changes in liver and kidney function) were seen, 
including changes in serum phosphate levels.
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Histopathological changes at 60 mg/kg/day included mineralization of the aorta and stomach 
(glandular portion) and other effects in the colon/cecum and lymph nodes. The mineralization 
seen is likely to be related to the pharmacology of ASTX029. Widespread mineralization 
affecting the stomach, kidney, colon, and arteries has been described to be related to MEK 
inhibition through FGF-23 signal blockade (Diaz 2012; Yanochko et al 2013). The resulting 
increased levels of the active form of vitamin D (1,25-dihydroxyvitamin D3) and, in turn, of Ca 
and P are considered the cause of metastatic calcification (Diaz 2012; Yanochko et al 2013). 
Although no changes in serum Ca and P were seen in the GLP study in rats, they were seen in 
the preceding DRF studies, and changes in these cations are considered relevant to the proposed 
pathogenesis of soft tissue calcification seen in this study. Based on the DRF studies, high doses 
of 60 mg/kg/day for males and 50 mg/kg/day for females were selected as the top doses for GLP 
studies to account for the gender difference in exposure and sensitivity. 
In the pivotal rat GLP study, ASTX029 administered orally to male and female Sprague Dawley 
rats QD for 28 consecutive days at 0, 6, 18, 50 (females), or 60 (males) mg/kg/day caused 
morbidity and severe clinical signs including scabs and body weight loss at the high dose of 
50 mg/kg/day in females with 6 animals prematurely euthanized between Days 19 and 22. The 
rest of the group were either euthanized on Day 22 or assigned to the recovery group with no 
further doses administered. In males given 60 mg/kg/day, 2/15 males were also euthanized on 
Day 22 in poor condition, showing decreased body weight. At the high dose, which was clearly 
above tolerated level for the duration of this study, histopathology changes were present in 
multiple organs with the changes being grouped into soft tissue mineralization affecting the 
gastrointestinal (GI) tract, arterial system throughout, and the kidneys; degenerative ulcerative 
changes in the tongue and GI tract; bone and marrow changes due to infection and remodeling as 
a consequence of altered mineral homeostasis; and degenerative changes in the liver in the form 
of necrosis and inflammation. Hepatic periportal hypertrophy was also present. 
Changes in hematology (indicative of anemia and inflammation) and clinical chemistry 
parameters (liver and kidney function parameters) were consistent with those seen in the DRF 
studies in rats given the high dose. Microscopic findings in the high dose (above levels of 
tolerability) animals were extensive and severe, with a number of target organs being identified 
that included the aorta, stomach, and colon/cecum (as seen previously in the DRF studies), plus 
skin, bone, liver, and kidney. At the intermediate dose of 18 mg/kg/day, minimal changes in 
hematology and clinical chemistry parameters were seen, all of which were consistent with those 
seen in DRF studies and recovered by the end of the treatment-free period. Microscopically, the 
only target organ in rats given 18 mg/kg/day was the skin, with lesions, seen only in females at 
this dose, that did not fully recover by the end of the 2-week treatment-free period. Based on the 
severity of the skin lesions in females given 18 mg/kg/day and the lack of findings in males, the 
no-observable adverse effect level (NOAEL) was considered to be 18 mg/kg/day, with systemic 
exposures on Day 28 in males of maximum concentration (Cmax) 138 ng/mL and area under the 
plasma concentration-time curve from the start of dosing (0) to the last quantifiable time point (t) 
(AUC0-t) 1,860 ng•h/mL and in females of Cmax 3,340 ng/mL and AUC0-t of 14,700 ng•h/mL. 
Given the difference in sensitivity between males and females at doses 18 mg/kg/day and above, 
the severely toxic dose in 10% of the animals (STD10) (defined as the highest dose level that 
does not produce evidence of lethality, life-threatening toxicities, or irreversible findings) was 
considered to be above 18 but below 50/60 mg/kg/day. The exposure ratios for Cmax and AUC0-t 
were 0.01 and 0.14 for male rats and 0.25 and 1.13 for female rats, respectively, relative to 
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average exposures from the lowest dose tested (25 mg/kg) and shown to be efficacious in 
xenograft mouse studies (Colo205). 
In dogs, repeat-dose toxicity was first evaluated in a DRF study of 14 day’s duration using QD 
dosing, followed by a pivotal 28-day GLP study using continuous QD dosing (plus a 2-week 
recovery period). In the DRF study, morbidity/early terminations occurred at the highest dose 
tested (16 and 30 mg/kg/day, respectively, in male and female dogs) manifested by severe 
clinical signs and reduced body weight, suggesting males to be more sensitive to the toxic effects 
of ASTX029, albeit with limited number of animals (1 per dose) evaluated. This was reflected in 
the higher systemic exposures achieved in males versus females for a given dose. Key findings 
were changes in hematology and clinical chemistry parameters consistent with those seen in 
studies with rats. Macroscopically, findings were seen in the gastric mucosa of the stomach. The 
maximum tolerated dose (MTD) was considered to be ≥12 mg/kg/day in this study, but given the 
longer duration of the GLP study, the high dose of 10 mg/kg/day was selected for the pivotal 
4-week toxicology study. In the DRF study, the dose level of 12 mg/kg/day in the male dog was 
associated with Cmax and AUC0-t values of 32,400 ng/mL and 120,000 ng•h/mL, respectively, on 
Day 14. For the female dog receiving 16 mg/kg/day, the Cmax and AUC0-t values on Day 14 were 
24,200 ng/mL and 66,800 ng.hr/mL, respectively.
In the pivotal GLP dog study, dose levels were 0, 1.5, 3.5, and 10 mg/kg. One male at the mid-
dose of 3.5 mg/kg/day was euthanized early on Day 20 due to severe clinical symptoms and 
body weight loss. Microscopic evaluation revealed significant findings in the GI tract that were 
believed to be the cause of the clinical condition of the animal leading to early termination. 
Exposure achieved in in this animal was high for the group, overlapping with those achieved at 
the highest dose of 10 mg/kg/day. In animals surviving to scheduled termination, key findings 
included changes in hematology parameters consistent with anemia and inflammation, changes 
in coagulation parameters (increased fibrinogen), and minimal changes in clinical chemistry 
(decreased albumin at ≥1.5 mg/kg/day and total protein at 10 mg/kg/day). The ECG 
measurements revealed incidence of second degree AV block in 1 female and premature 
ventricular complex in another female dog given 10 mg/kg/day on scheduled measurement on 
Day 23. A second measurement taken on Day 29 showed the same findings (but in reverse with 
respect to the 2 animals affected). These animals were retained for further measurements at the 
end of the recovery period and showed no findings. In this study, the period of recording was 
short (1 to 2 minutes), and these arrhythmias are also reported to be common background 
findings in beagle dogs (Cools et al 2011; Tilley 1992). The incidences of arrhythmias observed 
in this study with ASTX029 were within ranges reported in normal dogs. Of note, dogs have 
high cardiac vagal tone compared to humans and sinus arrhythmia and sinus pauses can be quite 
pronounced in normal dogs (Cools et al 2011). Second degree AV block is also found in normal 
animals and is often associated with sinus arrhythmia and high vagal tone (Cools et al 2011). The 
potential for ASTX029-related cardiac arrhythmia was further investigated in a dedicated 
standalone GLP cardiovascular safety pharmacology study in dogs, in which some evidence for 
this was seen, with 1 dog showing high incidence of arrhythmias at the high dose (30 mg/kg. 
However, this animal did not receive other doses or vehicle treatment in the study and, as such, 
although a clear relationship to study treatment could not be conclusively established, based on 
available evidence from both studies, a relationship to ASTX029 could not be completely ruled 
out since they were only observed in animals in the high dose group.
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In the dog pivotal study, ASTX029-related microscopic findings were present in the esophagus 
and spleen. In 1 female dog, given 10 mg/kg/day, inflammation and ulceration were seen in the 
esophagus, which may have correlated with episodes of vomiting recorded on Days 17 and 18 in 
this animal and were considered adverse due to the severity. In addition, extramedullary 
hematopoiesis was observed in both sexes at 10 mg/kg/day and correlated with changes in 
hematology parameters indicative of anemia. This change was considered to be a physiological 
response to the anemia and, therefore, was considered nonadverse. Overall, based on the 
nontolerability seen at 3.5 mg/kg/day in 1 male dog, the highest non-severely toxic dose 
(HNSTD) was considered to be 1.5 mg/kg/day, which also coincided with the NOAEL for this 
study. The exposure ratios for Cmax and AUC0-t were 0.51 and 1.04 for male dogs and 0.07 and 
0.21 for female dogs, respectively, relative to average exposures from the lowest dose tested 
(25 mg/kg) and shown to be efficacious in xenograft mouse studies (Colo205).
Although the toxicities seen and target organs identified at the NOAEL dose in rats (mid-dose 
level, skin) and HNSTD/NOAEL in dogs (low-dose level, GI tract), these dose levels in these 
species were toxicologically meaningful as they produced toxicities that have been seen with 
compounds in this class. More severe toxicities observed at higher dose levels that were above 
tolerability are likely also explained by exaggerated pharmacology consistent with class effect. 
With the exception of the 1 dog at the intermediate dose (3.5 mg/kg) level that terminated early 
due to severe clinical signs explained by severe GI toxicities, other findings in the dog study 
were minimal including those in animals from the high-dose level, and were fully recovered 
following the 2-week treatment-free period. However, in rats, the high dose (60 mg/kg in males 
or 50 mg/kg in females) was clearly not tolerated due to a multitude of target organs being 
affected due to exaggerated pharmacology as well as secondary infections due to severe skin 
lesions. 
Data from a bacterial reverse mutation test in Salmonella typhimurium and Escherichia coli 
(“Ames test”), an in vivo mammalian erythrocyte micronucleus test in the mouse, an in vitro 
chromosomal aberration assay in human peripheral blood lymphocytes reveal no evidence of 
genotoxicity. 
In conclusion, the main findings in toxicity evaluation studies in both species tested were 
consistent with the expected pharmacological action of ASTX029 (ie, findings in bone, soft 
tissue mineralization, skin lesions, and ulceration of the GI tract). Other findings, such as 
minimal effects on liver function with no associated histopathology correlates, may be due to the 
chemical toxicity of ASTX029. For an ERK inhibitor, tissue mineralization is a known class 
effect relating to perturbation of phosphate handling linked to vitamin D levels and FGF-23 
inhibition (Diaz et al 2012; Yanochko et al 2013). In addition, delayed skin lesions (rash) have 
also been seen clinically with ERK and MEK inhibitors (Sullivan et al 2018; Li et al presentation 
2017; Varga et al 2020; MacDonald et al 2015; Manousaridis et al 2013). Since the lower (in 
terms of human equivalent dose) NOAEL (and the HNSTD) was seen in the dog, this species is 
considered more sensitive than the rat to the toxicity of ASTX029 based on dose alone. 
However, considering the overlapping observed systemic exposures in rat and dog pivotal 
studies at the HNSTD in dogs and the NOAEL in rats and also the apparent gender differences 
seen in both species, the distinction of the dog as the more sensitive species is tentative. In 
addition, some key findings in the rats (tissue mineralization, skin lesions), which are consistent 
with known class effects of MAPK pathway inhibitors, can be considered relevant to the clinic. 
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Therefore, due to the overlapping exposures at toxicologically meaningful doses in rats and dogs, 
both species have been considered for calculation of the proposed starting dose for the FIH 
clinical trial.
1.3.3.
Clinical Data and Human Pharmacokinetics
This is an FIH study for ASTX029. For current data, please refer to the ASTX029 IB.
1.4.
Summary of Data for Other Study Treatment 
This is a clinical study of ASTX029 as a single agent (monotherapy). No active control 
treatments are planned.
1.5.
Potential Risks and Benefits to Human Subjects
The MAPK pathway is a key regulator of cellular proliferation and survival. Somatic alterations 
in MAPK pathway components that deregulate the pathway are highly prevalent in human 
cancer (Santarpia et al 2012; Kim and Choi 2010; Dhillon et al 2010; Roberts and Der 2007). 
Agents targeting the MAPK pathway (eg, BRAF and MEK inhibitors) have demonstrated 
clinical efficacy and have attained regulatory approval for BRAF-mutated metastatic melanoma 
(Bollag et al 2012) and BRAF mutated NSCLC (FDA 2017). Recently, several ERK inhibitors 
have entered clinical testing (https://clinicaltrials.gov/); however, none have yet attained 
regulatory approval.
In the FIH Phase 1-2 trial of the ERK inhibitor ulixertinib at oral doses up to 900 mg 
administered twice a day (BID), treatment-related dose limiting toxicities (DLTs) included Grade 
3 rash, Grade 3 pruritus, Grade 3 aspartate aminotransferase (AST) elevation, Grade 3 and Grade 
2 diarrhea, Grade 3 vomiting, Grade 3 dehydration, Grade 3 elevated creatinine, and Grade 2 
hypotension. At the recommended Phase 2 dose (RP2D) of 600 mg BID, ulixertinib was 
commonly associated with cutaneous adverse events (AEs) (rash, pruritus, dermatitis acneiform, 
and dry skin), GI AEs (diarrhea, nausea, and vomiting), decreased appetite, fatigue, and 
peripheral edema (Sullivan et al 2018; Li et al presentation 2017; Infante et al abstract 2015; 
Infante et al presentation 2015), with 32% of subjects requiring dose reductions. One event each 
of retinal vein occlusion (RVO) and cardiac failure and 2 events of acute renal failure were 
reported. Responses were observed in subjects with typical and atypical BRAF mutations and 
NRAS mutations.
In an FIH Phase 1 trial of another ERK inhibitor, GDC-0994 at oral doses up to 800 mg once a 
day for the first 21 days of a 28-day cycle, was associated with rash, diarrhea, visual 
disturbances, and asymptomatic LVEF decrease. At the RP2D of 400 mg, GDC-0994 was 
commonly associated with cutaneous AEs (rash, dry skin, and dermatitis acneiform); GI AEs 
(diarrhea, nausea, and vomiting), decreased appetite, fatigue, visual disturbances (blurred vision) 
and peripheral and periorbital edema (Varga et al 2020). Responses were observed in 2 subjects 
with CRC and BRAF mutations.
This study represents the first use of ASTX029 in humans, and, as with any investigational 
medicinal product (IMP), subjects may experience reactions or complications that are unknown 
and, therefore, unpredictable. Risks to subjects participating in this first evaluation of ASTX029 
in a human clinical trial include the potential for adverse reactions. Due to its mechanism of 
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action, ASTX029 may have a toxicity profile similar to that of other ERK inhibitors in clinical 
development with the main findings in toxicity evaluation studies in both species tested being 
consistent with the expected pharmacological action of ASTX029, ie, findings in bone, soft 
tissue mineralization, skin lesions, and ulceration of the GI tract, and the main findings at the 
STD10/NOAEL dose in rats and HNSTD dose in dogs being skin lesions (rats), GI lesions (dogs), 
and potential arrhythmias based on unconfirmed evidence from studies in dogs at higher doses 
(ASTX029 IB).
The potential for these AEs warrants frequent monitoring of subjects participating in this 
Phase 1-2 study of ASTX029 until the safety profile is further understood. In particular, clinical 
signs and/or symptoms of skin, ocular, GI, and liver toxicities and LVEF decrease (see 
Appendix 4, Appendix 5, Appendix 6, Appendix 7, and Appendix 8, respectively) as well as 
hematology and clinical chemistry parameters will be closely monitored during clinical studies 
that employ ASTX029.
These and other risks of ASTX029 in humans are described further in Section 8, 
Risks/Precautions. For more detailed information, please refer to the ASTX029 IB. 
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2.
RATIONALE
2.1.
Rationale for the Study
The MAPK pathway is a key regulator of cellular proliferation and survival. Somatic alterations 
in MAPK pathway components that deregulate the pathway are highly prevalent in human 
cancer (Dhillon et al 2007; Roberts and Der 2007). Activation of the ERK pathway in tumors can 
result from mutations in RAS genes (KRAS, NRAS, HRAS), mutations in BRAF and MEK, or 
activation of RAS by cell surface receptors (Nissan et al 2013).
The primary objectives of the Phase 1 portion of this study are to assess safety and to identify the 
MTD, the RP2D, and the recommended dosing regimen of ASTX029 administered orally. 
The primary objective of the Phase 2 portion of this study is to assess preliminary clinical 
activity, as determined by objective response rate (ORR) in tumors characterized by gene 
aberrations in the MAPK signal pathway that may confer sensitivity to ASTX029. 
2.2.
Rationale for ASTX029 Dose and Regimen and Justification of the 
Starting Dose
The starting dose for the FIH trial in cancer patients is proposed using available nonclinical data, 
following ICH and FDA Guidance S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, 
dated March 2010 (FDA S9 2010), and using dose conversions in accordance with FDA 
Guidance Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics 
in Adult Healthy Volunteers, dated July 2005 (FDA 2005), using data from GLP studies in the rat 
and dog. As dose levels slightly above the NOAEL are possibly in the low end of the range of 
STD10 for rats as a conservative estimate, the NOAEL of 18 mg/kg derived from 28-day 
continuous daily dosing in rats corresponds to the human equivalent dose (HED) of 108 mg/m2, 
which, converted to a fixed dose based on an average body surface area (BSA) of 1.7 m2 and 
applying a 1/10th safety factor adjustment, suggests a starting human dose of 18.36 mg. The 
1.5 mg/kg NOAEL/HNSTD dose from the dog GLP study corresponds to an HED of 30 mg/m2 
and translates to approximately 8.5 mg fixed dose based on BSA conversion and applying a 1/6th 
adjustment (Table 1). 
Table 1:
Proposed Human Starting Dose
HED, mg/m2
Implied Starting Dose, 
mga
Proposed Starting Dose, 
mg (Fixed)
Rat NOAEL, 18 mg/kg
108
18.36
Dog NOAEL/HNSTD, 1.5 mg/kg
30
8.5
10
BSA=body surface area; HED=human equivalent dose; HNSTD=highest non-severely toxic dose; NOAEL=no-observable 
adverse effect level.
a Based on average human BSA of 1.70 m2 and applying a safety factor of 1/10 for STD10 and 1/6 for HNSTD (per ICH S9 
[FDA S9 2010]).
In view of the variability in the toxicokinetic data in the 28-day GLP studies and the overlapping 
exposures seen in rats and dogs at the NOAEL and HNSTD, a fixed dose of 10 mg is proposed 
for the starting dose in FIH clinical trials in cancer patients (ie, an intermediate dose between the 
implied starting doses calculated using dog and rat data but, conservatively, closer to the low end 
of the range).
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ASTX029 has been shown to be efficacious in immunocompromised mouse xenograft models. 
At the lowest dose tested of 25 mg/kg (Colo205) systemic exposures as measured by Cmax and 
AUClast in the range of 9,618 to 16,880 ng/mL and 8,553 to 17,490 ng•h/mL, respectively, 
produced significant tumor growth inhibition as well as maximum inhibition of the RSK 
pharmacodynamic biomarker. The averages of these exposure values, 13,249 ng/mL for Cmax and 
13,022 ng•h/mL for the AUClast, were used for exposure comparisons with toxicokinetic data 
from toxicology studies. However, in xenograft studies following oral administration at 
25 mg/kg, ASTX029 caused near maximal inhibition of the phosphorylation of ribosomal S6 
kinase (RSK) in Colo205 tumors and, on repeat administration, produced significant tumor 
growth inhibition. Therefore, inhibition of extracellular signal-regulated kinases (ERK) is also 
anticipated at lower doses and lower exposures (AUC) of ASTX029.
The proposed clinical starting dose of 10 mg is less than 1/50th of projected human dose of 
500 mg estimated to produce AUC exposures in the presumed targeted therapeutic range, 
assuming translation from immunocompromised xenograft mouse pharmacology models. 
As in most targeted cancer therapy with kinase inhibitors, a continuous target engagement 
through continuous dosing is usually recommended, which will be the first regimen tested for 
ASTX029. However, ERK inhibitors are predicted to have a narrow therapeutic window when 
given continuously; therefore, an intermittent regimen (2 weeks on/1 week off) may also be 
tested in this FIH study. The regimen may be further adjusted (eg, 1 week on/1 week off) based 
on emerging clinical data and DSRC recommendations.
The rationale for the RP2D and regimen is discussed in Section 7.3.
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3.
STUDY OBJECTIVES
3.1.
Primary Objectives

Phase 1 (Parts A and B): To assess safety and to identify the MTD, the RP2D, and the 
recommended dosing regimen of ASTX029. 

Phase 2: To assess preliminary clinical activity, as determined by ORR in tumors 
characterized by gene aberrations in the MAPK signal pathway that may confer 
sensitivity to ASTX029.
3.2.
Secondary Objectives

To determine the PK profile of ASTX029 including the food effect on PK parameters.

To evaluate other clinical activity parameters, such as duration of response (DOR), 
disease control rate (DCR), progression-free survival (PFS), and overall survival 
(OS).

To evaluate relevant pharmacodynamic markers and target engagement (ie, 
phosphorylated ribosomal s6 kinase [pRSK] inhibition) in tumor biopsies. 
3.3.
Exploratory Objectives

To identify and evaluate biomarkers of ASTX029 activity. 
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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design
This is an FIH, open-label, multicenter, Phase 1-2 study to assess the safety of ASTX029, 
determine the MTD, RP2D, and recommended dosing regimen for ASTX029, and to obtain 
preliminary clinical activity, PK, and pharmacodynamic data in subjects with advanced solid 
tumors for whom standard life-prolonging measures or approved therapies are not available. 
It is anticipated that up to 300 evaluable subjects will be enrolled in this study if the study fully 
enrolls both Phases 1 and 2. This includes approximately 120 subjects in Phase 1 at up to 
14 study centers in the US and Europe and up to approximately 180 evaluable subjects in 
Phase 2 at up to 30 study centers in North America and Europe. The expected study duration is 
approximately 5 years (61 months), including approximately 55 months for recruitment and 
approximately 6 months for safety follow-up. 
This study consists of 2 phases, as shown in the study schema below (Figure 2).
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Figure 2:
Study Schema
BRAF=B isoform of RAF kinase; CRC=colorectal cancer; DSRC=Data Safety Review Committee; FIH=first in human; 
GNA11=G protein subunit alpha 11; GNAQ=G protein subunit alpha q; KRAS=Kirsten RAS; MEK=mitogen-activated 
extracellular signal-regulated kinase; MTD=maximum tolerated dose; NRAS=neuroblastoma RAS; NSCLC=non-small cell lung 
cancer; PK=pharmacokinetic; RAS=rat sarcoma virus; QD=daily; RDE=recommended dose for expansion; RP2D=recommended 
Phase 2 dose.
Notes: After reaching MTD or RDE for Regimens 1 and 2, the DSRC will advise if it is appropriate to test an alternative 
intermittent regimen (Optional Regimen 3) and will recommend the dose and dosing regimen to be used. One or more dose levels 
(and regimens) may be studied in Phase 1 Part B to supplement available safety, PK, and/or clinical activity data and to evaluate 
target engagement in fresh tumor tissue biopsies. In Phase 2 Cohort D, the sponsor, with approval of the DSRC, may expand 
enrollment for a particular molecularly defined subpopulation in which the most number of responses are observed to 10 or 29 
subjects for better assessment of activity in that disease subpopulation (Optional Cohort D expansion). It is expected that no more 
than 2 subpopulations will be expanded in this manner.
ASXT029 was originally introduced into the clinic in the PiB form (Section 7.1.1) and 
administered under fed conditions (Section 7.1.5). Protocol Amendment 1.0 introduced the tablet 
dosage form (Section 7.1.6) when it became available. Protocol Amendment 2.0 introduced the 
evaluation of administration under fasted conditions during Phase 1 Part A dose escalation 
(Section 7.1.7).
At the time of writing Protocol Amendment 4.0, the COVID-19 pandemic is altering the way 
clinical studies are being conducted such that alternative measures are being implemented to 
ensure the safety of subjects and maintain the integrity of clinical trial data. Appendix 9 details 
information regarding potential modifications to the conduct of the study during the pandemic.
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4.1.1.
Phase 1
The Phase 1 portion of the study will consist of Parts A and B as follows:
Part A (Dose Escalation): The dose-escalation stage will identify the MTD of up to 2 dosing 
regimens of ASTX029 and the recommended dose for expansion (RDE), defined as either the 
MTD or a dose below the MTD that the DSRC agrees shows adequate safety, PK, and/or 
preliminary biological or clinical activity.
Subjects will receive 1 of up to potentially 2 ASTX029 dosing regimens. Subjects in Regimen 1 
will receive ASTX029 orally once a day on Days 1 through 21 of each 21-day cycle (Regimen 1; 
continuous dosing), and, if Regimen 2 is opened to enrollment, subjects in Regimen 2 will 
receive ASTX029 orally once a day on Days 1 through 14 of each 21-day cycle (Regimen 2; 
intermittent dosing, 2 weeks on/1 week off).
Initially, subjects will be allocated to Regimen 1 (continuous dosing). Subjects in the first cohort 
of Regimen 1 will receive a flat starting dose of 10 mg QD. Dose levels for subsequent cohorts 
will be determined by the DSRC. Planned initial escalation will be 100% (doubling the dose) 
until 160 mg. Smaller increments of dose escalation will be used above 160 mg. Dose doubling 
will also be discontinued if any 1 of the following occurs within a cohort:

1 subject experiences a DLT (Section 7.4).

Any study-drug-related clinically significant ≥Grade 2 AE not adequately managed or 
resolved to baseline or Grade 1 by supportive treatment that, per the DSRC, indicates 
further dose doubling would be potentially unsafe for future subjects.

Any study-drug-related AE or confluence of AEs that, per the DSRC, indicates 
further dose doubling would be potentially unsafe for future subjects.
After this point, dose escalation will then proceed in smaller increments (eg, by a 50% increase 
initially and an ~25% increase at the higher dose levels over the previous level) (Section 7.1.4) 
after review of all available safety, PK, and biomarker data from Cycle 1 in at least 3 subjects 
and approval by the DSRC. 
Also, after this point, the sponsor, with approval of the DSRC, will determine if Regimen 2 is to 
be opened for enrollment. Randomization to either Regimen 1 or Regimen 2 will begin if both 
regimens are open for enrollment. Should Regimen 2 be evaluated, based on safety and PK data 
from Regimen 1 and depending on the nature, timing, and severity of observed AEs, the dose for 
the first cohort of subjects enrolled to Regimen 2 may be escalated to the next level pending 
approval by the DSRC. If the MTD is reached in 1 regimen before the other regimen, all 
subsequent subjects will be enrolled, without randomization, to the remaining regimen until the 
MTD is determined for each regimen evaluated. 
After reaching MTD or RDE for Regimens 1 and 2, the DSRC will also advise if it is appropriate 
to test an alternative intermittent regimen (Optional Regimen 3, eg, 7 days on/7 days off) and 
will recommend the dose and dosing regimen to be used. The total dose per cycle for the new 
regimen will not exceed the total safe dose per cycle already established in the first 2 regimens. 
Dose levels and dosing regimens, the number of cohorts, and the number of subjects per cohort 
may be modified, as needed, in response to emerging data and recommendations from the 
DSRC.
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The starting dose in each regimen evaluated will be escalated stepwise in successive cohorts of at 
least 3 evaluable subjects each with additional allowed expansion to 6 subjects (standard 3+3 
study design) (Section 7.3) until the MTD is determined for each regimen. 
Dose-escalation/de-escalation decisions will be based on the occurrence of DLTs (defined in 
Section 7.4) during the first 21-day cycle of each dose level, and the recommendations of the 
DSRC following review of all available safety, PK, and biomarker data from the completed first 
cycle of at least 3 subjects in each cohort (as described in Section 7.3). The DSRC will also 
advise whether or not it is appropriate to proceed to Part B (Dose Expansion). 
Part B (Dose Expansion) will commence upon identification of the RDE for at least 1 regimen. 
The DSRC RDE decision will be based on all available safety, PK, biomarkers, and preliminary 
activity data from all cycles (including the potential for late or cumulative toxicity).
Part B (Dose Expansion): One or more dose levels (and regimens) may be studied in Phase 1 
Part B to supplement available safety, PK, and/or clinical activity data to establish the RP2D and 
to evaluate target engagement in fresh tumor tissue biopsies. Subjects will have to meet the 
following molecular eligibility criteria: documented activating gene mutations in BRAF (BRAF 
V600 mutation or activating atypical non-V600 aberrations), KRAS, NRAS, or HRAS. The in 
vitro diagnostic (IVD) medical devices used in this study to determine genetic abnormalities are 
appropriately registered for use. A total of 14 evaluable subjects will be treated at each 
dose/regimen selected. If more than 1 dose/regimen is open for enrollment, subjects will be 
randomized in a 1:1 ratio. The DSRC will advise when it is appropriate to proceed to Phase 2 
and will recommend the dose level and dosing regimen to be used. The RP2D decision by the 
DSRC will be based on all available PK, pharmacodynamic, safety, and preliminary activity data 
from all cycles (including the potential for late or cumulative toxicity). The RP2D could be the 
same or lower than the RDE. 
4.1.2.
Phase 2
The Phase 2 portion of the study will explore the preliminary single-agent antitumor activity of 
ASTX029 at the RP2D of the selected dosing regimen identified in Phase 1 Parts A and B in 
tumors characterized by gene aberrations in the MAPK signal pathway that may confer 
sensitivity to ASTX029. The Phase 2 part of the study will consist of the following up to 6 
cohorts:

Cohort A: NRAS-mutant melanoma.

Cohort B: KRAS-mutant or KRAS-amplified NSCLC.

Cohort C: BRAF V600-mutant cancers (non-CRCs).

Cohort D: BRAF-fusion cancers.

Cohort E: Gynecological cancers with alterations in the MAPK pathway.

Cohort F: Tumors characterized by other gene aberrations that upregulate the MAPK 
signal pathway listed in Table 2.
Molecular eligibility will be based on the presence of documented gene aberrations in the MAPK 
pathway. The selection of these molecularly defined study populations is based on a 
comprehensive evaluation of ASTX029 nonclinical biology (as presented in the current 
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ASTX029 IB) and available literature (Table 2). In the first stage (Stage 1), 10 evaluable subjects 
will be enrolled into each cohort based on a Simon’s Optimal 2-stage design (Simon 1989) at the 
RP2D and the dosing regimen identified in Phase 1 Parts A and B. If ≥2/10 responses are 
observed in a cohort, it will be expanded to a total of 29 subjects (Stage 2). For Cohort F (which 
will enroll patients with various tumor types and gene aberrations [Table 2]), the sponsor, with 
approval of the DSRC, may expand enrollment for a particular molecularly defined 
subpopulation in which the most number of responses are observed to 10 or 29 subjects under the 
same Simon’s Optimal 2-stage design as for the other cohorts for better assessment of activity in 
that disease subpopulation (Optional Cohort F Expansion). It is expected that no more than 
2 subpopulations will be expanded in this manner.
Table 2:
Gene Aberrations Selected for Inclusion in Cohort F
Gene Aberration
Rationale
References
Activating HRAS mutations
ERK activity is commonly upregulated in cancer 
as a result of activating mutations within the 
RAS family of GTPases (KRAS, NRAS, and 
HRAS). 
Kiessling et al 2015
Prior et al 2012
Activating GNA11 and GNAQ 
mutations
Activating mutations in the heterotrimeric 
G protein alpha subunit q (GNAQ) and 11 
(GNA11) confer activation of the MAPK 
pathway.
Ambrosini et al 2012
Van Raamsdonk et al 
2009
Atypical activating BRAF 
aberrations
Atypical (non-V600E) BRAF mutations can 
signal as constitutively active dimers (class 2) 
and can confer activation of the MAPK pathway.
BRAF variants with in-frame deletions in the 
β3-αC-loop (ie, within or adjacent to residues 
L485-P490) can confer constitutive activation of 
BRAF.
Yao et al 2015
Chen et al 2016
Foster et al 2016
Activating MEK mutation
Activating MEK mutations confer upregulation 
of MAPK signaling.
Marks et al 2008
BRAF= B isoform of RAF kinase; ERK= extracellular signal-regulated kinase; GNA11= G protein alpha subunit 11; GNAQ=G 
protein alpha subunit q; GTPase=guanosine-5'-triphosphate enzyme; HRAS=Harvey RAS; KRAS=Kirsten RAS; 
MAPK=mitogen-activated protein kinase; MEK=mitogen-activated extracellular signal-regulated kinase; NRAS= 
neuroblastoma RAS; RAS=rat sarcoma virus.
Note: Other gene aberrations that in the investigator’s opinion may confer sensitivity to ASTX029 may be included in Cohort F 
after obtaining approval from the Sponsor’s medical monitor.
For each potential subject, there is an up to 21-day screening and eligibility assessment period 
before enrollment; the first dose of study treatment will be administered on Cycle 1 Day 1 
(C1D1). Subjects will continue to receive their assigned treatments throughout the study until the 
occurrence of disease progression, death, or unacceptable treatment-related toxicity; they elect to 
discontinue study treatment or withdraw consent to continue study participation; or until the 
study is closed by the sponsor. 
Study visits will take place weekly during Cycles 1 and 2 and less frequently thereafter (see 
Table 11 and Table 12 for the complete schedules of events for the Regimen 1 and Regimen 2, 
respectively). Serial blood samples will be collected for PK and biomarker analyses at specified 
time points. If a formalin-fixed paraffin-embedded (FFPE) archived tumor biopsy is available, it 
will be obtained for use in this study during screening. In addition, in Phase 1 Part A and 
Phase 2, fresh tumor biopsies are optional during screening and posttreatment during Cycle 2. In 
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Phase 1 Part B, fresh tumor biopsies are mandatory during screening and posttreatment during 
Cycle 2.
Upon permanent discontinuation of study treatment, there is a Treatment Termination (Tx Term) 
visit and a 30-day (±5 days or within 3 days before starting new treatment) Safety Follow-up 
visit. Subjects who remain on study after the 30-day Safety Follow-up visit will be contacted 
periodically by telephone for collection of long-term health status information. 
Tolerability and safety of study treatment will be evaluated throughout the study by collection of 
clinical and laboratory data. Antitumor response will be assessed according to standard Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 using computed tomography (CT) or 
magnetic resonance imaging (MRI) scans. Subjects whose disease is not measurable using 
RECIST v1.1 will be evaluated using another appropriate method.
4.2.
Discussion of Study Design
Phase 1 Part A of the study uses a standard dose-escalation design for an FIH study of a new 
anticancer IMP. The primary objectives of the Phase 1 portion of this study are to assess safety, 
and to identify the MTD of up to 2 dosing regimens of ASTX029, the RP2D, and the 
recommended dosing regimen of ASTX029 in subjects who became refractory or relapsed after 
treatment with available therapies and/or for whom standard life-prolonging measures or 
approved therapies are not available. The primary objective of the Phase 2 portion of the study is 
to assess preliminary clinical activity, as determined by ORR in tumors characterized by gene 
aberrations in the MAPK signal pathway that may confer sensitivity to ASTX029. Other 
objectives of the study are to determine the PK profile of ASTX029 administered orally and to 
evaluate other clinical activity parameters, such as DOR, DCR, PFS, and overall survival (OS); 
to evaluate relevant pharmacodynamic markers and target engagement (ie, phosphorylated pRSK 
inhibition) in tumor biopsies; and identify and evaluate potential biomarkers of ASTX029 
activity. This study is open-label, with no placebo or active control group.
The Phase 1 Part A dose-escalation process will be guided by safety and PK data and input from 
the DSRC (see Section 4.4, Section 7.3, and Section 7.4). The starting dose in each regimen 
evaluated will be escalated stepwise in successive cohorts of at least 3 subjects each with 
additional allowed expansion to 6 subjects (3+3 study design) until the MTD is determined for 
each regimen (see Section 4.1.1). 
Phase 1 Dose Expansion (Part B) will commence upon identification of the RDE for at least 
1 regimen. One or more dose levels (and regimens) may be studied in Phase 1 Part B to 
supplement available safety, PK, and/or clinical activity data to establish the RP2D and to 
evaluate target engagement in fresh tumor tissue biopsies. 
The Phase 2 portion of the study will explore the preliminary single-agent antitumor activity of 
ASTX029 at the RP2D of the selected dosing regimen identified in Phase 1 Parts A and B.
At any point, the dose level may be reduced for individual subjects in the event of unacceptable 
treatment-related toxicity (Section 7.5).
Planned dose levels and dosing regimens, the number of cohorts, and the number of subjects per 
cohort may be modified, as needed, in response to emerging data and recommendations from the 
DSRC.
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Initially, patients with any type of solid tumor will be eligible for enrollment in this study. In 
later parts of this study (ie, Phase 1 Part B and Phase 2), preliminary single-agent antitumor 
activity of ASTX029 will be assessed in tumors characterized by gene aberrations in the MAPK 
signal pathway that may confer sensitivity to ASTX029 (Section 4.1.2 and Table 2).
ASXT029 was originally introduced into the clinic in the PiB form (Section 7.1.1) and 
administered under fed conditions (Section 7.1.5). Protocol Amendment 1.0 introduced the tablet 
dosage form (Section 7.1.6) when it became available. Protocol Amendment 2.0 introduced the 
evaluation of ASXT029 administration under fasted condition during Phase 1 Part A dose 
escalation (Section 7.1.7) as a result of data available from food-effect studies in animals 
(Section 1.3.2.1) and preliminary PK data available from Phase 1 Part A (Section 7.1.7).
4.3.
Study Endpoints
4.3.1.
Primary Endpoints

Phase 1: Incidences of DLTs and AEs to determine the MTD of up to 2 dosing 
regimens of ASTX029 and the RP2D and regimen to be taken to Phase 2.

Phase 2: Clinical activity assessed by ORR according to RECIST v1.1 criteria. 
4.3.2.
Secondary Endpoint(s)

PK parameters of ASTX029, including AUC, Cmax, minimum concentration (Cmin), 
time to reach maximum concentration (Tmax), elimination half-life (t½), food effect on 
ASTX029 PK parameters, and other secondary PK parameters of ASTX029 if data 
permit; analysis of ASTX029 metabolites if applicable.

Inhibition of pRSK protein in response to ASTX029 treatment in tumor biopsies.

PFS.

OS.

DCR.

DOR.
4.3.3.
Exploratory Endpoint(s) 

Suppression of mutant clones in circulating tumor DNA (ctDNA).

Explore additional biomarkers of ASTX029 activity.
4.4.
Data and Safety Review Committee
For Phase 1, the DSRC will include the principal investigator at each study center; for Phase 2, 
the DSRC composition will be detailed in the DSRC charter. The DSRC for both phases will 
also include the Sponsor’s medical monitor and other subject matter experts (eg, clinical 
pharmacologist) as needed. The purpose of the DSRC is to review emerging safety, PK, 
pharmacodynamic, and preliminary clinical activity data, discuss any safety concerns, and 
recommend changes in the protocol intended to enhance the safety of subjects or increase the 
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chances that the study will meet its objectives. Unanimous recommendations for which the only 
purpose is to enhance the safety of subjects will be implemented immediately, and all 
investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) 
will be notified regarding such changes.
The DSRC will meet principally by teleconference at least once a month during Phase 1 and at 
least every 3 months during Phase 2. Additionally, during Phase 1 Part A, it will meet when 
complete Cycle 1 safety data are available from at least 3 subjects treated at the dose level and 
regimen being evaluated. After reviewing all available safety, PK, biomarker, and preliminary 
activity data from at least 3 subjects in each cohort, the DSRC will recommend either increasing 
the cohort size to 6 or proceeding with either dose escalation or reduction, as appropriate; it will 
also advise if recruitment into Regimen 2 may be initiated and the dose to be used and if an 
alternative regimen (Optional Regimen 3) is to be evaluated. The DSRC will also advise when to 
proceed to Part B (Dose Expansion) and when the Phase 2 portion of the study may be initiated 
and will recommend the dose and dosing regimen(s) to be used (RDE and RP2D for Phase 1 
Part B and Phase 2, respectively). 
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5.
SELECTION AND WITHDRAWAL OF SUBJECTS
5.1.
Number of Subjects and Centers
It is anticipated that approximately 300 evaluable subjects will be enrolled in this study if the 
study fully enrolls both Phases 1 and 2. This includes approximately evaluable 120 subjects in 
Phase 1 at up to 14 study centers in the US and Europe and up to approximately 180 evaluable 
subjects in Phase 2 at up to 30 study centers in North America and Europe. 
The number of cohorts in Phase 1 Parts A and B and the number of subjects per cohort will be 
based on emerging safety and PK data and recommendations from the DSRC. The number of 
subjects in Phase 2 will be based on clinical activity observed and recommendations from the 
DSRC. More subjects may be enrolled if more dose levels are tested in Part A of the study, if 
more than 1 cohort is selected for expansion in Part B or if more than the expected number of 
subpopulations in Cohort F of Phase 2 are expanded.
5.2.
Inclusion Criteria
To be eligible for the study, subjects must fulfill all of the following inclusion criteria:
1. Able to understand and comply with the study procedures, understand the risks involved 
in the study, and provide written informed consent before any study-specific procedure is 
performed.
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 and in the Phase 2 portion of the protocol, subjects 
must also have documented gene alterations in the MAPK pathway as detailed in 
Section 4.1.1, Section 4.1.2, and Table 2.
4. In Phase 1 Part B 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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
6. Eastern Cooperative Oncology Group performance status 0 to 2.
7. Acceptable organ function, as evidenced by the following laboratory data:
a.
AST and alanine aminotransferase (ALT) ≤2×upper limit of normal (ULN) or ≤3 
ULN in the presence of liver metastases.
b. Total serum bilirubin ≤1.5×ULN.
c.
Absolute neutrophil count (ANC) ≥1500 cells/mm3.
d. Platelet count ≥100,000 cells/mm3. 
e.
Calculated creatinine clearance (by the standard Cockcroft-Gault formula) of 
≥50 mL/min or glomerular filtration rate of ≥50 mL/min.
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8. Women of child-bearing potential (according to recommendations of the Clinical Trial 
Facilitation Group [CTFG]; see below* for details) must not be pregnant or breastfeeding 
and must have a negative pregnancy test (urine or serum as required by local regulations) 
within 24 hours before the first dose of study treatment. Women of child-bearing 
potential must agree to the following during the treatment period and for at least 32 days 
(approximately 5 half-lives of ASTX029 or metabolite plus 30 days) after receipt of last 
dose of study treatment:
a.
Refrain from donating eggs (ova, oocytes) for the purpose of reproduction.
b. Use a contraceptive method** that is highly effective with a failure rate of <1% per 
year), with low user dependency. The investigator should evaluate the effectiveness 
of the contraceptive method before the first dose of study treatment. The investigator 
is responsible for review of medical history, menstrual history, and recent sexual 
activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
9. Men with a pregnant partner or non-pregnant partner who is a woman of childbearing 
potential must agree to the following during the treatment period and for at least 92 days 
(approximately 5 half-lives of ASTX029 or metabolite plus 90 days) after receipt of last 
dose of study treatment:
a.
Refrain from donating sperm.
b. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and to remain abstinent OR to use a 
male condom when having sexual intercourse with a woman of childbearing potential 
(according to recommendations of the CTFG; see below* for details) who is not 
currently pregnant, and the female partner should be advised of the benefit of using 
an additional highly effective contraceptive method** with a failure rate of <1% per 
year as a condom may break or leak. The investigator should evaluate the 
effectiveness of the contraceptive method before the first dose of study treatment.
*According to recommendations of the CTFG (http://www.hma.eu /fileadmin/dateien 
/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2020_09_HMA_ 
CTFG_Contraception_guidance_Version_1.1_updated.pdf), a woman is considered of childbearing 
potential (ie, fertile) following menarche and until becoming postmenopausal, unless permanently 
sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy.
**Contraceptive measures that may be considered highly effective comprise combined hormonal 
contraception (oral, vaginal, or transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, sexual abstinence, and surgically successful 
vasectomy. Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of birth control.
5.3.
Exclusion Criteria
Subjects meeting any of the following criteria will be excluded from the study:
1. Hypersensitivity to ASTX029 or excipients of the drug product. 
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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:
a.
Cytotoxic chemotherapy or radiotherapy within 3 weeks prior. Palliative radiotherapy 
to a single lesion within 2 weeks prior. Any encountered treatment-related toxicities 
(excepting alopecia) not stabilized or resolved to ≤Grade 1.
b. Monoclonal antibodies or biologics within 4 weeks prior. Any encountered treatment-
related toxicities not stabilized or resolved to ≤Grade 1.
c.
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 (excepting alopecia) not stabilized or resolved to ≤Grade 1.
5. Prior treatment with ERK inhibitors. 
6. History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following 
conditions:
a.
Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram 
(ECHO) or multiple-gated acquisition (MUGA) scan. 
b. Congestive cardiac failure of ≥Grade 3 severity according to New York Heart 
Association (NYHA) functional classification defined as patients with marked 
limitation of activity and who are comfortable only at rest.
c.
Unstable cardiac disease including unstable angina or hypertension as defined by the 
need for overnight hospital admission within the last 3 months (90 days).
d. 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 (AV) block, presence of cardiac pacemaker or 
defibrillator, or other significant arrhythmias.
e.
Screening 12-lead ECG with measurable QTc interval of ≥470 msec. (Fridericia's 
formula should be used to calculate the QTc interval throughout the study.)
7. Known history of human immunodeficiency virus (HIV) infection or seropositive results 
consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) 
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.
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10. History or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR) including:
a.
Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or 
ocular hypertension, uncontrolled diabetes mellitus) or
b. 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.
5.4.
Treatment Discontinuation and Withdrawal of Subjects
Subjects who discontinue study treatment will be followed up for important study data, as 
described below, unless they withdraw consent from further follow-up.
5.4.1.
Discontinuation From Study Treatment
Subjects may permanently discontinue study treatment at any time (note: subjects who 
experience disease progression while receiving ASTX029 should not remain on study 
treatment). Subjects who discontinue study treatment will still continue study follow-up 
procedures until death, or until they withdraw consent or the study is closed. Investigators are 
encouraged to assess all subjects according to the study protocol even after discontinuation from 
study treatment. Possible reasons for discontinuation of study treatment include the following:

Investigators can discontinue subjects from study treatment in case of unacceptable 
toxicity, non-compliance, disease progression requiring alternative therapy, or if the 
investigator determines it is in the subject's best interest. 

The Sponsor may require that a subject is discontinued from treatment for safety 
reasons or for noncompliance. 
In all cases, the reason(s) for discontinuation from study treatment must be recorded in the 
source document and on the relevant page of the subject's electronic case report form (eCRF). 
It is important to obtain protocol-specified follow-up information on any subject discontinued 
from study treatment. For subjects who discontinue study treatment, the investigator should 
review the follow-up procedures with the subject, including the number of visits, the specific 
procedures to be done, and the total length of the follow-up period. If at all possible, subjects 
should undergo all safety and preliminary clinical activity evaluations at the Tx Term visit 
(Section 9.4.13) and the 30-day Safety Follow-up visit (Section 9.4.14). Section 10 describes 
follow-up for AEs. At minimum, subjects should be followed up for safety until 30 days after the 
last dose of study treatment (see Section 10.3). 
Subjects who agree to remain enrolled in the study after discontinuing study treatment and 
completing the 30-day Safety Follow-up visit will be contacted by telephone for health status 
information every 3 months until death, withdrawal of consent, or the end of study, whichever 
occurs first (see Section 9.4.15).
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5.4.2.
Withdrawal From the Study
Subjects may withdraw consent for the study at any time or subjects may be lost to follow-up. It 
is important to obtain follow-up information, according to standard medical practice, on any 
subject withdrawn prematurely from the study. Every effort must be made to undertake at least 
standard assessments that are critical for clinical activity or safety evaluation, such as disease 
progression (if the subject did not withdraw because of disease progression), subsequent 
anticancer treatment, survival information, and safety data. 
If a subject withdraws consent from the study, the sponsor may retain and continue to use any 
information and data collected or generated up to the time of withdrawal of consent.
Additionally, if a subject withdraws consent, they may request destruction of any samples taken 
and not tested yet, and the investigator must document this in the site study records and inform 
the sponsor within 24 hours.
5.4.3.
Replacement of Subjects
Subjects will be replaced in this study as needed to achieve the planned number of evaluable 
subjects in each part of the protocol. See Section 11.1 for the definition of evaluable subjects.
5.4.4.
End of Study
The study will be considered complete (that is, scientific evaluation will be complete [study 
completion]) following evaluation of safety and efficacy as determined by the Sponsor. 
Investigators will continue to follow the Schedule of Activities (Table 13) for all patients until 
notified by the Sponsor that study completion has occurred. 
End of the study is the date of the last visit or last scheduled procedure for the last patient.
5.4.5.
Study Extension
Following Study Completion (see above Section 5.4.4), all patients who are on study treatment 
and deriving clinical benefit with no undue risk may continue to receive study treatment in a 
study extension phase or a rollover study until any of the study treatment discontinuation criteria 
(Section 5.4.1) are met.
During study extension, assessments are to be conducted according to the Schedule of Activities 
in Table 13. Data collection will be limited and will include (at a minimum):

Study drug administration

Study drug accountability

AEs

SAEs

Any cases of pregnancy or overdose
Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion. The 
Sponsor will not routinely collect the results of these assessments.
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If an SAE occurs, the Sponsor may request additional information (eg, local laboratory results, 
concomitant medications, hospitalizations) to evaluate the reported SAE.
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6.
ENROLLMENT AND RANDOMIZATION PROCEDURES
Subjects will be screened at each study center for assessment of eligibility for the study. The 
investigator or designated staff will be responsible for allocating and recording subject 
identification numbers. Each subject who signs the informed consent form (ICF) will be assigned 
a unique identification (ID) number that reflects the study center number assigned to the 
investigator and the subject at that site. The same subject ID number will be used to identify the 
subject from screening throughout the study and will be entered on all study documents.
A given subject ID number will not be assigned to more than 1 subject. If a subject is not eligible 
to receive treatment or if the subject discontinues from the study, the subject number will not be 
reassigned to another subject. A centralized allocation procedure will be used. 
See Section 7.3 for the dose-escalation guidelines.
6.1.
Randomization
This is an open label study. All enrolled subjects will receive ASTX029. In Phase 1 Part A (dose 
escalation), initially, only a single dosing regimen (Regimen 1) will be evaluated. Following the 
occurrence of event(s) meeting prespecified criteria (Section 7.1.4), a second dosing regimen 
(Regimen 2) may be activated. If the second dosing regimen becomes active, subjects will be 
assigned following a simple randomization procedure (eg, computerized random numbers) to 
Regimen 1 (continuous dosing) or Regimen 2 (intermittent dosing).
When only a single regimen is active (eg, the cohort for 1 regimen has completed enrollment, or 
is on hold), randomization will be suspended, and all subjects will be allocated to the active 
regimen.
In Phase 1 Part B, if more than 1 dose/regimen is selected, subjects will be randomized in a 1:1 
ratio.
When a qualified subject is identified (ie, meets all eligibility criteria), site staff will confirm the 
subject’s eligibility in the Interactive Response Technology (IRT) system. The IRT system will 
automatically enroll/randomize the subject to the appropriate treatment regimen/cohort and 
allocate study drug. Details of randomization/enrollment are described in the IRT User Guide.
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7.1.3.
ASTX029 Reconstitution 
Tablets are provided in bottles containing 21 tablets each. A sufficient quantity of tablets will be 
dispensed to the subject to permit oral self-administration at the required dose level for the 
required number of days.
Records of the receipt and dispensing of drug will be kept at the study centers and reconciled at 
the end of the study to provide a complete accounting of all used and unused IMP.
7.1.4.
ASTX029 Regimens and Dose Levels
In this open-label study, all subjects will receive ASTX029 orally according to the assigned 
treatment regimen and dose. At any point in the study, the dose of ASTX029 may be reduced, 
withheld, or discontinued for individual subjects in the event of unacceptable treatment-related 
toxicity, as described in Section 7.5. No active comparator or placebo is planned for this study.
In Phase 1 Part A, subjects will receive 1 of up to potentially 2 ASTX029 dosing regimens. 
Subjects in Regimen 1 will receive ASTX029 orally once a day on Days 1 through 21 of each 
21-day cycle (Regimen 1; continuous dosing), and, if Regimen 2 is opened to enrollment, 
subjects in Regimen 2 will receive ASTX029 orally once a day on Days 1 through 14 of each 21-
day cycle (Regimen 2; intermittent dosing, 2 weeks on/1 week off).
Initially, subjects will be allocated to Regimen 1 (continuous dosing). Subjects in the first cohort 
of Regimen 1 will receive a flat starting dose of 10 mg QD (Section 2.2). Dose levels for 
subsequent cohorts will be determined by the DSRC. Planned initial escalation will be 100% 
(doubling the dose) until 160 mg. Smaller increments of dose escalation will be used above 
160 mg. Dose doubling will also be discontinued if any 1 of the following occurs within a 
cohort:

1 subject experiences a DLT (Section 7.4).

Any study-drug-related clinically significant ≥Grade 2 AE not adequately managed or 
resolved to baseline or Grade 1 by supportive treatment that, per the DSRC, indicates 
further dose doubling would be potentially unsafe for future subjects.

Any study-drug-related AE or confluence of AEs that, per the DSRC, indicates 
further dose doubling would be potentially unsafe for future subjects.
After this point, dose escalation will proceed in smaller increments (eg, by a 50% increase 
initially and an ~25% increase at the higher dose levels over the previous level), after review of 
all available safety, PK, and biomarker data from Cycle 1 in at least 3 subjects and approval by 
the DSRC. The DSRC will determine the need to expand to 6 subjects per cohort if 1 subject in 
the first 3 subjects or if multiple subjects have Grade 2 events that require additional subjects in 
order to collect additional safety data and better inform dose-escalation decisions. If more than 
1 subject has DLTs in any cohort of 3 or 6 subjects, no further escalation should occur of that 
regimen and exploration of lower dose regimens may be recommended by the DSRC to refine 
the MTD and the RDE.
An example of a possible dose-escalation plan is shown in Table 3, and a possible dose 
escalation flowchart is shown in Figure 3.
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Table 3:
Example of Possible ASTX029 Dose Levels in Part A
Cohort
Dose Level
(mg/day)
Number of Evaluable 
Subjects Planned
Comments
1
10 mg
3 or 6
Starting dose based on toxicology data
(Section 2.2)
2
20 mg
3 or 6
Increase Starting dose by 100%
3
40 mg
3 or 6
Increase Cohort 2 dose by 100%
4
80 mg
3 or 6
Increase Cohort 3 dose by 100%
5
160 mg
3 or 6
Increase Cohort 4 dose by 100%
6
240 mg
3 or 6
Increase Cohort 5 dose by 50%
7
360 mg
3 or 6
Increase Cohort 6 dose by 50%
8
450 mg
3 or 6
Increase Cohort 7 dose by 25%
Note: The dose levels and escalation shown in this table are for purposes of example only. The Data and Safety Review 
Committee will decide on actual dose levels and may recommend escalation increments based on emerging safety and 
pharmacokinetic data or operational concerns. Planned initial escalation will be 100% (doubling the dose) until 160 mg. 
Smaller increments of dose escalation will be used above 160 mg.
Figure 3:
ASTX029-01 Phase 1 Part A Dose Escalation Flowchart
AE=adverse event; DLT=dose-limiting toxicity; DSRC=Data and Safety Review Committee; MTD=maximum tolerated dose; 
RDE=recommended dose for expansion; TBD=to be determined.
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See Section 7.3 for dose-escalation guidelines.
Also, after this point, the sponsor, with approval of the DSRC, will determine if Regimen 2 is to 
be opened for enrollment. Randomization to either Regimen 1 or Regimen 2 will begin if both 
regimens are open for enrollment. Should Regimen 2 be evaluated, based on safety and PK data 
from Regimen 1 and depending on the nature, timing, and severity of observed AEs, the dose for 
the first cohort of subjects enrolled to Regimen 2 may be escalated to the next level pending 
approval by the DSRC. If the MTD is reached in 1 regimen before the other regimen, all 
subsequent subjects will be enrolled, without randomization, to the remaining regimen until the 
MTD is determined for each regimen evaluated. 
After reaching MTD or RDE for Regimens 1 and 2, the DSRC will also advise if it is appropriate 
to test an alternative intermittent regimen (Optional Regimen 3, eg, 7 days on/7 days off) and 
will recommend the dose and dosing regimen to be used. The total dose per cycle for the new 
regimen will not exceed the total safe dose per cycle already established in the first 2 regimens.
The starting dose in each regimen evaluated will be escalated stepwise in successive cohorts of at 
least 3 evaluable subjects each with additional allowed expansion to 6 subjects (3+3 study 
design) until the MTD is determined for each regimen.
Dose-escalation/de-escalation decisions will be based on the occurrence of DLTs (defined in 
Section 7.4) during the first 21-day cycle of each dose level, and the recommendations of the 
DSRC following review of all available safety, PK, and biomarker data from the completed first 
cycle of at least 3 subjects in each cohort (as described in Section 7.3). The DSRC will also 
advise whether or not it is appropriate to proceed to Part B (Dose Expansion).
Part B (Dose Expansion) will commence upon identification of the RDE for at least 1 regimen. 
The DSRC RDE decision will be based on all available safety, PK, biomarkers, and preliminary 
activity data from all cycles (including the potential for late or cumulative toxicity).
At any point, the dose level may be reduced for individual subjects in the event of unacceptable 
treatment-related toxicity (Section 7.5). Planned dose levels, the number of cohorts, and the 
number of subjects per cohort, may be modified as needed, in response to emerging PK and 
safety data, and recommendations from the DSRC.
7.1.5.
ASTX029 Administration
Subjects will receive instructions for the storage and self-administration of the IMP by oral 
administration at home (also see Section 9.4.11). However, on visit days, subjects will be asked 
to wait until they arrive at the study center and are under the supervision of the study staff before 
they ingest the study drug to ensure accurate recording and timing of blood draws relative to IMP 
ingestion. When subjects self-administer IMP at home, they are expected to record the date and 
time of ingestion in their dosing diary, along with any pertinent notes (eg, vomiting after 
ingestion of the dose). 
If a patient forgets to take or misses a dose, they may take the dose up to 4 hours late. After that 
time, the patient should skip the dose for that day and wait until the next day to resume the 
normal dosing schedule. The VFR of ASTX029 contains ethanol and propylene glycol (Section 
7.1.1). The maximum amount of the alcohol intake from the VFR is estimated to be 3.7 g. (Refer 
to the pharmacy manual for further information.)
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ASTX029 should be ingested at approximately the same time of day on each dosing day, and the 
actual dosing time should be recorded as above. 
Study treatment compliance will be assessed periodically throughout the treatment period. 
Subjects will be required to return all study treatment syringes (used, unused, and partially used) 
and all unused tablets to the study center, and to share their dosing diaries with study staff. 
ASXT029 was originally introduced into the clinic in the PiB form (Section 7.1.1) and 
administered under fed conditions (Section 7.1.5). Protocol Amendment 1.0 introduced the tablet 
dosage form (Section 7.1.6) when it became available. Protocol Amendment 2.0 introduced the 
evaluation of administration under fasted conditions during Phase 1 Part A dose escalation 
(Section 7.1.7).
Drug Administration Under Fed Conditions
Based on available preliminary data and the properties of ASTX029, it was expected that doses 
would be better tolerated and absorbed when consumed with food. Hence, although food-effect 
studies had not yet been conducted with ASTX029, subjects enrolled in the early stages of dose 
escalation were requested to ingest the IMP with food, ie, within 30 minutes after a breakfast 
meal. Subjects receiving ASTX029 under fed conditions are requested to have a balanced 
breakfast meal. Examples of breakfast meals are:

Egg(s), toast (or potatoes), and juice (orange, apple, cranberry, or tomato) or 
coffee/tea.

Bacon (2 strips), toast (or potatoes), and juice (as above) or coffee/tea.

Sausage, toast (or potatoes), and juice (as above) or coffee/tea.

Breakfast sandwich with eggs/sausage/bacon; juice (as above) or coffee/tea.
Other varieties/substitutions can be made as long as the meal provides a similar amount of 
calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity. 
Note: grapefruit juice is not allowed during treatment with ASTX029. 
Drug Administration Under Fasted Conditions
Amendment 2.0 introduced the evaluation of fasted administration during Phase 1 Part A. 
Subjects receiving ASTX029 under fasted conditions will be requested to ingest the study 
treatment after fasting for at least 2 hours, typically in the morning before breakfast, and to also 
fast for 2 hours after ingestion of study drug. During the 4-hour fasting period, clear liquids (such 
as tea, coffee, and water) are allowed; milk, juice, and soup are not allowed. Note: grapefruit 
juice is not allowed during treatment with ASTX029. Please see Section 7.1.7 for further 
details of transition to fasted administration during Phase 1 Part A.
7.1.6.
Transition From Powder-in-Bottle Dosage Form to Tablet Dosage Form
With Protocol Amendment 1.0, the tablet form was introduced and replaced the PiB formulation. 
Transition to the tablet dosage form occurred by dosing a tablet-bridging cohort of 6 subjects at 
80 mg/day, a dose that did not exceed the highest PiB dose level in Regimen 1 at which no DLTs 
were observed as determined by the DSRC assessment of all safety and PK data at the time of 
initiation of the tablet-bridging cohort. Because the tablet dose was shown to be safe and no 
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other issues were identified, dose escalation using the tablet dosage form proceeded in 
subsequent cohorts as described in Section 4.1.1, Table 3, with approval of the DSRC. If the 
tablet dosing form had not been safely tolerated, dose de-escalation could have occurred as 
described in Section 7.3 and Section 7.5. Based on review of safety and PK data, the DSRC 
could have allowed transition of ongoing subjects still receiving PiB to tablets. At the time of 
Amendment 4.0, all subjects who received ASTX029 PiB had discontinued study drug.
7.1.7.
Transition From Fed to Fasted Administration
At the time of Amendment 2.0, dose escalation (Phase 1 Part A) was ongoing. In Phase 1 Part A, 
ASXT029-01 dose was escalated in sequential cohorts from 10 mg/day to 200 mg/day QD using 
the PiB form in fed subjects. One DLT (Grade 3 nonserious maculo-papular rash) was reported 
in the 200-mg/day PiB cohort. Six subjects were enrolled in the tablet-bridging cohort at 
80 mg/day QD under fed conditions with no DLTs being reported, and enrollment was ongoing 
in the 120-mg/day QD tablet cohort. 
Preliminary PK data at the time of Amendment 2.0, showed relatively high variability for 
systemic exposures after ASTX029 was dosed with food. The geometric mean (CV%) plasma 
AUC0-inf values on C1D1 were 2377(170) ng•h/mL for the 80-mg tablet-bridging cohort (n=4), 
compared with 4053(83) ng•h/mL for the 120 mg PiB (n=5) cohort and 8304(53) ng•h/mL for 
the 200 mg PiB cohort (n=9).
With Protocol Amendment 2.0, administration under fasted conditions was introduced. Fasted 
administration may result in higher exposure of ASTX029 at lower doses (Section 1.3.2.1) and 
potentially reduce intersubject variability compared with administration with food. 
Transition to fasted-state dosing occurred during Phase 1 Part A by dosing a bridging cohort of 
3 subjects at a dose of 40 mg/day tablets QD. Starting with Amendment 3.0, dose escalation 
under fed conditions was discontinued, and dose escalation under fasted conditions is ongoing. 
Please refer to the current ASTX029 IB for preliminary PK and safety data.
7.2.
Active Comparator or Placebo
No active comparator or placebo is planned for this study.
7.3.
Dose-Escalation Guidelines and Recommended Phase 2 Dose 
Decision
Dose-escalation/de-escalation decisions will be based on the occurrence of DLTs (defined in 
Section 7.4) during the first cycle of each dose level, and the recommendations of the DSRC 
following review of all available safety, PK, and biomarker data from the completed first cycle 
of at least 3 subjects in each cohort (Section 4.4). The DLT-based dose-escalation guidelines are 
summarized below.
Intrasubject escalations will not be allowed; however, once an MTD or RDE dose level is 
determined, active subjects may be allowed to receive their subsequent cycles at that dose level 
at the investigator’s discretion with prior Sponsor approval.
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First 3 Subjects in a Cohort

If no subjects among the first 3 (<33%) experience a DLT, the dose may be escalated 
to the next higher level for the next cohort of 3 subjects.

If 1 subject among the first 3 (33%) experiences a DLT, the cohort size will be 
increased to 6 subjects.

If 2 subjects among the first 3 (>33%) experience a DLT, the previous dose level (ie, 
1 step below) would be declared the MTD. 
Expanded Cohort of 6 Subjects

If no more than 1 subject in the cohort of 6 (ie, a total of 1 out of 6, <33%) experience 
a DLT, the dose may be cautiously escalated (~25% increase) to the next higher level 
for the next cohort of 3 subjects.

If 2 subjects in the cohort of 6 (33%) experience a DLT, that dose level or the 
previous dose level (ie, 1 step below) would be declared the MTD for the regimen. 
The DSRC may recommend exploration of intermediate doses before an MTD is 
declared.

If more than 2 subjects in the cohort of 6 (>33%) experience a DLT, the previous 
dose level (ie, 1 step below) would be declared the MTD for the regimen. The DSRC 
may recommend exploration of intermediate doses before an MTD is declared.
Recommended Dose for Expansion
The RDE is defined as either the MTD or a dose below the MTD that the DSRC agrees shows 
adequate safety, PK and/or preliminary biological activity, or clinical activity for a regimen. One 
or more dose levels (and regimens) may be studied in Phase 1 Part B to supplement available 
safety, PK, and/or clinical activity data and to evaluate target engagement in fresh tumor tissue 
biopsies. The RDE decision by the DSRC will be based on all available safety, PK, biomarkers, 
and preliminary activity data from all cycles (including potential for late or cumulative toxicity) 
from Phase 1 Part A.
Recommended Phase 2 Dose
The RP2D is defined as the dose that the DSRC agree shows adequate safety, PK, 
pharmacodynamic, and/or biological or clinical activity to warrant further investigation in the 
Phase 2 part of this study. The RP2D decision by the DSRC will be based on all available PK, 
biomarker, safety, and preliminary clinical activity data from all cycles, including potential for 
late or cumulative toxicity from Phase 1 Parts A and B. The RP2D could be the same or lower 
than the RDE.
Based on the data presented in Section 1.3.3, the DSRC determined the RP2D to be 200 mg 
administered orally daily, continuously, in 21-day cycles under fasting conditions.
7.4.
Definition of Dose-Limiting Toxicities
Dose-limiting toxicities are AEs (graded by National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria [Appendix 2]) that occur 
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during the first cycle of treatment and represent any 1 of the following, unless there is a clear 
alternative cause of the event (eg, disease progression, disease-related): 

Grade 4 thrombocytopenia of any duration.

≥Grade 3 hematologic toxicity with complications (eg, Grade 3 thrombocytopenia 
with bleeding or transfusion requirement).

Febrile neutropenia of any duration or Grade 4 neutropenia of 5 days or more 
duration.

Liver-associated abnormalities defined as:

≥Grade 3 bilirubin, ALT, or AST elevation, except ALT or AST elevation 
>5×ULN and <8×ULN for <7 days. 

ALT or AST >3×ULN AND either total bilirubin >2×ULN OR international 
normalized ratio (INR) >1.5. 

ALT or AST >3×ULN with clinical indications of liver toxicity (signs, symptoms, 
or other diagnostic findings). 

≥Grade 2 eye disorders (ocular toxicities) that do not improve to ≤Grade 1 within 
7 days despite treatment discontinuation or documented RVO. 

Symptomatic Grade 2 cutaneous toxicities (including skin rash) that do not improve 
to ≤Grade 1 within 7 days despite supportive treatment and treatment discontinuation. 

Any other ≥Grade 3 nonhematologic AE except Grade 3 nausea, vomiting, or 
diarrhea that resolves to ≤Grade 1 by symptomatic treatment within 24 hours.

Any event that, in the opinion of the DSRC, would suggest that further dose 
escalation would put subjects at unacceptable risk.
7.5.
Guidelines for Adjusting, Withholding, or Discontinuing Study 
Treatment
ASTX029 dosing should be withheld in the case of a DLT in Cycle 1 or toxicity in subsequent 
cycles that would have qualified as a DLT if it had occurred in Cycle 1. Dosing may resume, at 
the investigator’s discretion, if and when study-treatment-related toxicity has:

Completely resolved or 

Returned to baseline or partially recovered to ≤Grade 2 (anemia, fatigue, malaise, and 
alopecia) or returned to baseline or partially recovered to ≤Grade 1 (all other 
toxicities).
If and when a decision is made to resume dosing, the individual’s dose should be adjusted to the 
previously assessed lower dose level that was considered safe by the DSRC. A maximum of 
2 dose reductions are permitted for any single subject. In the event of further unacceptable 
toxicity, the investigator should consider discontinuation of study treatment for that subject.
If toxicity has not resolved as described above within 21 days, the investigator should 
permanently discontinue study treatment unless the subject is receiving compelling benefit, the 
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benefit of the study treatment exceeds the risks, and no alternative therapy is available. Approval 
by the Sponsor’s medical monitor is required to restart study treatment after an interruption 
≥21 days, and study treatment must be administered at a dose approved by the Sponsor’s medical 
monitor when toxicity has resolved as described above.
Suggested guidelines and criteria for adjusting, withholding, or discontinuing study treatment as 
a result of skin toxicities, ocular toxicities, diarrhea, liver toxicities, and LVEF decrease are 
provided in Appendix 4, Appendix 5, Appendix 6, Appendix 7, and Appendix 8, respectively. 
The institutional standards for the management of these toxicities can differ from the suggested 
guidelines. In this case, best clinical judgment should be applied.
7.6.
Concomitant Treatment
On the concomitant medication eCRF, document all medications a subject takes starting from 
14 days before study treatment initiation and ending 30 days after the last dose of study 
treatment. Include supportive or palliative treatment (see below) whether prescription or 
nonprescription, and medications taken for procedures (eg, biopsy). Include start and stop dates 
and indication. 
7.6.1.
Supportive, Prophylactic, or Other Treatments
All subjects receiving treatment with ASTX029 should continue to receive appropriate 
supportive care for the treatment of their cancer, according to the institutional standard practice 
or other established standard of care guidelines. Antiemetics and loperamide may be given to 
alleviate ASTX029-related toxicity on an as-required basis, and GI toxicity should not be 
considered to be dose limiting in the absence of maximal supportive therapy. Subjects receiving 
treatment with a bisphosphonate are not excluded from participating in the trial; bisphosphonate 
therapy may be initiated while maintaining treatment with ASTX029 provided the subject does 
not have disease progression according to RECIST v1.1 criteria. The subject may receive 
palliative radiotherapy to a symptomatic lesion during the study. All efforts should be made to 
reduce the radiation field to the smallest possible area of exposure. ASTX029 treatment should 
be interrupted during radiotherapy and resumed upon completion. 
Any supportive treatment should be documented in the provided eCRFs.
7.6.2.
Prohibited Medications and Substances
Other anticancer treatments, including other investigational drugs or therapies, unless specified 
in the protocol, are prohibited. 
ASTX029 is a substrate and inhibitor of cytochrome P450, family 3, subfamily A (CYP3A). 
Therefore, concomitant administration of drugs known to be strong CYP3A4 inhibitors or 
inducers has the potential to result in drug-drug interactions (DDIs) with ASTX029. Careful 
consideration should be given to balancing the medical needs of the subject and the potential 
effect on ASTX029 before coadministering a drug that is known to be a strong CYP3A4 
inhibitor or inducer. It is strongly recommended that subjects avoid strong CYP3A4 inhibitors 
and inducers at ASTX029 dose levels that display clinical effects (toxicity or activity). Particular 
caution should be exercised when coadministering drugs with ASTX029 that are sensitive 
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CYP3A substrates with narrow therapeutic windows until the potential liability of ASTX029 for 
DDIs is fully qualified. 
ASTX029 is an inhibitor of the liver uptake transporter OATP1B1. Therefore, concomitant 
administration of drugs known to be OATP1B1 substrates has the potential to result in DDIs 
with ASTX029. Particular caution should be exercised when coadministering drugs with 
ASTX029 that are sensitive OATP1B1 substrates with narrow therapeutic windows until the 
potential for DDIs via inhibition of OATP1B1 is fully understood.
Examples of CYP3A4 inhibitors and inducers and OATP1B1 substrates and inhibitors may be 
found on the following websites; note that the published lists are not comprehensive. Refer to the 
specific product information for an intended concomitant drug.

FDA.gov: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm093664.htm (FDA 2020).

Pharmacytimes.com: 
http://www.pharmacytimes.com/publications/issue/2015/december2015/drug-
interactions-with-cyp3a4-an-update (Horn and Hansen 2015). 
Medications known to increase the risk of torsades de pointes should be used with caution. A list 
of such medications is provided at the following website and discussed in Drew et al (2010), 
https://www.crediblemeds.org/ (Woosley et al 2022). Any AV-nodal blocking medications (ie, 
beta-blockers, non-dihydropyridine calcium-channel blockers, and digitalis) should be used with 
caution. A list of such medications is provided and discussed in Wooten 2002 and by Vogler et al 
(Vogler et al 2012).
The VFR of ASTX029 contains ethanol and propylene glycol (Section 7.1.1). It is advisable to 
review concomitant medications that may interact with VFR ingredients.
Any medication considered necessary for the subject’s safety and well-being may be given at the 
discretion of the investigator(s). However, if a subject requires treatment with a drug known to 
prolong the QT interval while on study and there is no alternative medication, the subject should 
be carefully monitored for potential QT prolongation for at least 24 hours. Investigators should 
also be aware that the list of medications that prolong the QT interval provided in the cited 
references is not exhaustive and there are other medications with a possible or conditional risk of 
causing QT prolongation and/or torsades de pointes. 
Investigators should consult with the Sponsor’s medical monitor regarding the potential 
concomitant use of QTc-prolonging agents with a known risk of torsades de pointes while on 
study treatment in individual subjects on a case-by-case basis.
Concomitant St. John’s Wort, grapefruit, and grapefruit juice are also prohibited during 
treatment with ASTX029.
7.7.
Overdose Instructions
Record the actual dose of study drug administered in the source document and on the Dosing 
eCRF. Record any adverse clinical signs and symptoms associated with a potential overdose on 
the AE eCRFs. Report signs and symptoms of a potential overdose that meet SAE criteria 
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(defined in Section 10.1.2) to the Sponsor’s Pharmacovigilance group or its designee within 
24 hours from the time the investigator first becomes aware of the SAE (see Section 10.2.4). 
Treat any AE (including SAE) based on standard care for the specific signs and symptoms. 
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8.
RISKS/PRECAUTIONS
Refer to the ASTX029 IB for the most current risks and precautions, as well as a list of potential 
AEs associated with ASTX029 therapy based on nonclinical toxicology studies and clinical 
findings with other investigational agents in this drug class. 
This study represents the first use of ASTX029 in humans, and as with any investigational 
medicinal product (IMP), subjects may experience reactions or complications that are unknown 
and therefore unpredictable. Risks to subjects participating in this first evaluation of ASTX029 in 
a human clinical trial include the potential for adverse reactions. 
Based on nonclinical toxicology studies with this molecule, and clinical findings with other 
investigational agents in this drug class (ERK inhibitors; ie, ulixertinib and GDC-0994) (Sullivan 
et al 2018; Li et al presentation 2017; Varga et al 2020; Infante et al abstract 2015; Infante et al 
presentation 2015), the ASTX029 mechanism of action may result in cutaneous AEs (eg, rash, 
pruritus, dry skin), GI AEs (eg, diarrhea, nausea, vomiting, and esophagitis), fatigue, peripheral 
and periorbital edema, LVEF decrease, potential arrhythmias, visual disturbances, and liver 
enzyme elevation.
The potential for these AEs warrants frequent monitoring of subjects participating in clinical 
trials of ASTX029 until the safety profile is further understood. In particular, clinical signs 
and/or symptoms of cutaneous, ocular, GI, and liver toxicities and LVEF decrease will be closely 
monitored, evaluated, and managed during the study (Appendix 4, Appendix 5, Appendix 6, 
Appendix 7, and Appendix 8 respectively).
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9.
STUDY ASSESSMENTS AND PROCEDURES
9.1.
Preliminary Clinical Activity Assessments
Measurable disease according to RECIST v1.1 (Appendix 3) will be assessed using CT or MRI 
scans at baseline (screening), every 2 cycles (±7 days) for the first 4 cycles, and then every 4 
cycles (±1 cycle) thereafter until clinical and/or radiographic disease progression, death, or the 
subject withdraws consent. Tumor markers (if applicable) should be measured at the same time 
points as the time points for radiological assessments.
For subjects whose disease is not measurable using RECIST v1.1, disease status must be reliably 
and consistently followed using another generally acceptable method. 
9.2.
Pharmacokinetic/Pharmacodynamic/Biomarker Assessments
9.2.1.
Pharmacokinetic Assessments
Serial blood samples for Phase 1 will be collected over a 24-hour period at specified time points 
postdose for PK analysis on C1D1, Cycle 1 Day 2 (C1D2), Cycle 2 Day 1 (C2D1), and Cycle 2 
Day 2 (C2D2) for Regimen 1 (Table 4) and on C1D1, C1D2, Cycle 1 Day 14 (C1D14), and 
Cycle 1 Day 15 (C1D15) for Regimen 2 (Table 5). 
Serial blood samples for Phase 2 will be collected on C1D1, C1D2, C2D1, and Cycle 3 Day 1 
(C3D1) for Regimen 1 (Table 6) and on C1D1, C1D2, C1D14, C1D15, and C3D1 for Regimen 2 
(Table 7). 
Additional ad hoc blood sample(s) may be collected, per investigator discretion, for PK 
measurement at any time, including after the last dose, if there is a suspected safety issue.
ASTX-029 plasma concentration data will be used to determine PK parameters, including AUC, 
Cmax, Cmin, Tmax, and t½, in all subjects initially during Cycle 1 (both regimens) and Cycle 2 
(Regimen 1), if data are evaluable. Metabolites of ASTX029 may be investigated if applicable. It 
is essential that the actual time and date of sample collection relative to the administration of 
study treatment be recorded in the subject's eCRF. Nominal PK blood sampling times and 
collection windows should be adhered to as closely as possible. 
During the course of the study, as data emerge and improve the understanding of PK of 
ASTX029, sample collection times may be modified. Blood sample preparation and plasma 
sample storage details are provided in the laboratory manual.
Table 4:
Phase 1: Plasma Collection Schedule for Pharmacokinetic Analysis 
(Regimen 1)
Study Day
Dosing Day?
Time Pointa
Hours Postdose 
C1D1
Yes
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m)b, 3.0 (±10 m), 
4.0 (±10 m), 6.0 (±20 m), 
8.0 (±30 m)
C1D2
Yes
24 ±1.0 h after C1D1 dose 
(prior to C1D2 dose)
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Study Day
Dosing Day?
Time Pointa
Hours Postdose 
C2D1
Yes
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m)b, 3.0 (±10 m), 
4.0 (±10 m), 6.0 (±20 m), 
8.0 (±30 m)
C2D2
Yes
24 ±1.0 h after C2D1 dose 
(prior to C2D2 dose) 
Ad hoc PK sample (including 
trough sample, ie, ~24 h post last 
dose if safety event suspected)
Per investigator discretion
CxDx=Cycle x Day x; ECG=electrocardiogram; h=hour(s); m=minute(s); PK=pharmacokinetic.
a On dosing days, collect predose samples within 60 minutes prior to administration of study treatment.
b It is recommended that the 2-hour postdose ECG be performed before PK sample collection.
Table 5:
Phase 1: Plasma Collection Schedule for Pharmacokinetic Analysis 
(Regimen 2)
Study Day
Dosing Day?
Time Pointa
Hours Postdose 
C1D1
Yesa
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m)b, 3.0 (±10 m), 
4.0 (±10 m), 6.0  (±20 m), 
8.0 (±30 m)
C1D2
Yesa
24 ±1.0 h after C1D1 dose 
(prior to C1D2 dose)
C1D14
Yesa
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m)b, 3.0 (±10 m), 
4.0  (±10 m), 6.0 (±20 m), 
8.0 (±30 m)
C1D15
No
24 ±1.0 h after C1D14 dose
Ad hoc PK sample (including 
trough sample, ie, ~24 h post last 
dose if safety event suspected)
Per investigator discretion
CxDx=Cycle x Day x; ECG=electrocardiogram; h=hour(s); m=minute(s); PK=pharmacokinetic. 
a On dosing days, collect predose samples within 60 minutes prior to administration of study treatment.
b It is recommended that the 2-hour postdose ECG be performed before PK sample collection.
Table 6:
Phase 2: Plasma Collection Schedule for Pharmacokinetic Analysis 
(Regimen 1)
Study Day
Dosing Day?
Time Pointa
Hours Postdose 
C1D1
Yes
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m)b, 3.0 (±10 m), 
4.0 (±10 m), 6.0 (±20 m), 
8.0 (±30 m)
C1D2
Yes
24 ±1.0 h after C1D1 dose 
(prior to C1D2 dose)
C2D1
Yes
Predose
2.0 (±10 m)b
C3D1
Yes
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m), 4.0 (±10 m), 
8.0 (±30 m)
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Study Day
Dosing Day?
Time Pointa
Hours Postdose 
Ad hoc PK sample (including 
trough sample, ie, ~24 h post last 
dose if safety event suspected)
Per investigator discretion
CxDx=Cycle x Day x; ECG=electrocardiogram; h=hour(s); m=minute(s); PK=pharmacokinetic.
a On dosing days, collect predose samples within 60 minutes prior to administration of study treatment.
b It is recommended that the 2-hour postdose ECG be performed before PK sample collection.
Table 7:
Phase 2: Plasma Collection Schedule for Pharmacokinetic Analysis 
(Regimen 2)
Study Day
Dosing Day?
Time Pointa
Hours Postdose 
C1D1
Yesa
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m)b, 3.0 (±10 m), 
4.0 (±10 m), 6.0  (±20 m), 
8.0 (±30 m)
C1D2
Yesa
24 ±1.0 h after C1D1 dose 
(prior to C1D2 dose)
C1D14
Yesa
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m)b, 3.0 (±10 m), 
4.0  (±10 m), 6.0 (±20 m), 
8.0 (±30 m)
C1D15
No
24 ±1.0 h after C1D14 dose
C3D1
Yes
Predose
0.5 (±5 m), 1.0 (±5 m), 
2.0 (±10 m), 4.0 (±10 m), 
8.0 (±30 m)
Ad hoc PK sample (including 
trough sample, ie, ~24 h post last 
dose if safety event suspected)
Per investigator discretion
CxDx=Cycle x Day x; ECG=electrocardiogram; h=hour(s); m=minute(s); PK=pharmacokinetic. 
a On dosing days, predose samples are to be collected within 60 minutes prior to administration of study treatment
b It is recommended that the 2-hour postdose ECG be performed before PK sample collection.
9.2.2.
Pharmacodynamic and Biomarker Assessments
Assessment of target engagement and biomarker analyses will be performed in blood and tumor 
tissue biopsies. Biomarker investigations will include the following: 

Demonstration of target engagement in fresh tumor tissue biopsies (when available) 
(eg, pRSK and pERK inhibition following ASTX029 treatment).

Evaluation of cancer cell proliferation and induction of apoptosis in fresh tumor tissue 
biopsies (when available).

Suppression of mutant clones in ctDNA.

Identification of potential biomarkers of ASTX029 activity (DNA, RNA, or protein) 
in blood and tumor tissue biopsies (archival and fresh biopsies, when available).
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Biomarker analyses will be performed by methods including immunohistochemistry, reverse 
transcription polymerase chain reaction (RT-PCR), next-generation sequencing, and possibly 
others.
Blood samples will be collected for biomarker analysis at the time points indicated in Table 8. 
Details of blood sample collection and handling procedures are provided in the laboratory 
manual.
If a FFPE archived tumor tissue is available, it will be obtained for use in this study during 
screening. In addition, collection of new (or fresh) tumor biopsies is encouraged (optional) in 
Phase 1 Part A and Phase 2 and mandatory in Phase 1 Part B of the study at the time points 
indicated in Table 9.
Archived tissue and fresh biopsies collected at screening will be used to characterize the genetic 
background of the tumor, confirm mutational status, and identify potential additional biomarkers 
of response to ASTX029; biopsies collected on treatment will be used to establish target 
engagement in tumor tissue and changes induced by ASTX029 treatment. At each time point (if 
safe and feasible), at least 2 biopsy cores will be collected (1 to be fresh-frozen and 1 to be 
FFPE). The subject must sign a biopsy ICF. A posttreatment biopsy sample need not be collected 
if a pretreatment biopsy (fresh) is not available for comparison. Details of biopsy tissue 
collection and handling procedures are provided in the laboratory manual. 
Table 8:
Sample Collection Schedule for Biomarker Analyses
Study Day
Dosing Day?
Samples
Time Point
Screening
No
Germline DNA (PBMC), 
ctDNA
C1D1
Yes
ctDNA
Predosea
C2D1
Yes
ctDNA
Predosea
Day 1 of every cycle thereafter
Yes
ctDNA
Predosea
Treatment Termination visit
No
ctDNA
CxDx=Cycle x Day x; ctDNA=circulating tumor DNA; PBMC=peripheral blood mononuclear cell.
a On dosing days, predose samples are to be collected within 60 minutes prior to administration of study treatment.
Table 9:
Tumor Tissue Collection Schedule for Biomarker Analyses
Study Day
Dosing Day?
Samples
Time Point
Archival
No
FFPE
Screening
No
FFPE, Frozen
C2D8 (±1 day) 
Yes
FFPE, Frozen
4.0 h (±1 h) postdose
C2D8=Cycle 2 Day 8; h=hour(s); FFPE=formalin-fixed paraffin embedded.
If archived tumor tissue (FFPE) is available, it will be requested for use in this study during screening. In addition, collection of 
fresh tumor biopsies is encouraged (optional) in Phase 1 Part A and Phase 2, and mandatory in Phase 1 Part B.
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9.2.3.
Total Volume of Blood Samples to Be Drawn
The estimated amount of blood to be collected for PK, biomarker investigations, and routine 
monitoring of hematology, coagulation, and serum chemistry during any cycle will not exceed 
165 mL.
9.3.
Safety Assessments
At each study visit, safety will be monitored by recording AEs, SAEs, DLTs, and concomitant 
medications; additional assessments that may be performed at selected visits include complete or 
symptom-directed physical examinations (PEs), weight, height, vital signs, ECOG performance 
status, 12-lead ECGs, clinical laboratory tests (including hematology, serum chemistry, 
urinalysis, and other tests [coagulation tests] as applicable), and ECHO/MUGA scans (see 
Table 11 and Table 12 for the complete schedules of events for Regimen 1 and Regimen 2, 
respectively). General information regarding the definition, evaluation, recording, and reporting 
of AEs and SAEs is provided in Section 10. Additional information regarding AEs specific to 
this protocol are provided below.
9.3.1.
Adverse Events
The AEs should be captured from the time of first dose until 30 days after the last dose of study 
treatment or the start of an alternative treatment, whichever occurs first. The AEs that occur 
during the screening period and are considered related to screening procedures, as well as all 
related SAEs occurring beyond 30 days from the last dose of study treatment, will also be 
captured. Any SAEs will be followed until they have resolved or are stable.
The following events will be recorded in the eCRF as AEs:

Adverse events of any severity grade (including changes from screening). 

Clinically significant abnormal findings during clinical assessments, including PEs 
and vital signs.

Clinically significant abnormal ECG readings and any clinically significant 
ECHO/MUGA results.

Spontaneous subject reports.

Baseline medical conditions and AEs, other than the primary disease under 
evaluation, that worsen in severity or frequency during the study. 
Clinical hematology, coagulation, serum chemistry, and urinalysis results that are outside of 
normal ranges but are not considered by the investigator to be clinically significant will not be 
reported as AEs.
9.4.
Study Procedures
9.4.1.
Physical Examination 
Complete or symptom-directed PEs should be performed during the course of the study as 
outlined in the schedules of events (Section 9.4.9). At screening, a complete PE will be 
performed per the institutional standard practice but must include a skin examination. After 
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screening, symptom-directed PEs will be performed at the time points indicated in the schedules 
of events and at the investigator’s discretion. The subject's height and weight should be measured 
and recorded at screening, and the subject’s weight should be recorded on Day 1 of each cycle.
If a clinically significant abnormality is observed, the investigator will record it as part of the 
subject's medical history if it occurs prior to the start of study treatment on C1D1 and as an AE if 
it occurs after the commencement of study treatment.
9.4.2.
Vital Signs
At screening and predose at the time points specified in the schedules of events (Section 9.4.9), 
resting systolic and diastolic blood pressure, resting heart rate, resting respiration rate, and body 
temperature are to be recorded; postdose at the specified time points, resting blood pressure and 
heart rate are to be recorded.
Assess vital signs after the subject has rested in a sitting or semirecumbent position for at least 
3 minutes.
On each study day, blood pressure and heart rate will be measured using a blood pressure 
recording device with an appropriate cuff size. The date and time of collection and 
measurements will be recorded on the appropriate eCRF.
9.4.3.
ECOG Performance Status
ECOG performance status (Appendix 1) should be assessed at screening and during the course of 
the study at the time points outlined in the schedules of events (Section 9.4.9).
9.4.4.
12-Lead ECG
The 12-lead ECGs are to be performed at screening and predose and 2 hours (±30 minutes) 
postdose on C1D1 and C2D1 in Regimen 1 and on C1D1 and C1D14 in Regimen 2; the 12-lead 
ECGs are to be performed predose at all other time points on the dosing days and at the Tx Term 
visit as indicated in the schedules of events (Section 9.4.9). All ECGs will be recorded at 
25 mm/second in triplicate, with each recording separated by at least 30 seconds while the 
subject is resting in a semirecumbent position. Two copies of the ECG tracing should be 
obtained at the time of the ECG; the first copy will be kept in the subject’s medical chart and the 
second copy will be kept in the study file for retrospective collection by the sponsor if necessary.
The following ECG data will be collected: rhythm, atrial rate, ventricular rate, PR interval, QRS 
duration, QT/QTc, morphology, and overall interpretation. The QTc is measured as the mean of 
the 3 values. 
The investigator or designated physician will review the timed 12-lead ECGs on C1D1, before 
ASTX029-01 dosing to ensure ECG findings meet study entry criteria, and, otherwise within 
24 hours of when they are collected, unless a critical value is observed. If subjects have a 
clinically significant abnormal ECG reading following treatment with ASTX029, their 
electrolytes should be checked and, if appropriate, serum potassium, calcium, and magnesium 
levels corrected and concomitant medications should be reviewed. Subjects may be discharged, 
if appropriate, later in the day, providing their ECG findings are no longer clinically significant. 
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If a clinically significant abnormal finding is observed, the investigator will record it as part of 
the subject’s medical history if it occurs prior to the start of study treatment on C1D1 and as an 
AE if it occurs after the commencement of study treatment.
9.4.5.
ECHO or MUGA Scan
Echo or MUGA scan assessments will be performed at screening, every 2 cycles for the first 
4 cycles and every 4 cycles thereafter (±7 days), and at the Tx Term visit as outlined in the 
schedules of events (Section 9.4.9). The same diagnostic method should be used throughout the 
study.
If a clinically significant abnormal finding is observed, the investigator will record it as part of 
the subject’s medical history if it occurs prior to the start of study treatment on C1D1 and as an 
AE if it occurs after the commencement of study treatment.
9.4.6.
Ophthalmic Examination
Subjects will be required to have a standard ophthalmic examination performed by an 
ophthalmologist at screening. The exam will include indirect fundoscopic evaluation, visual 
acuity (with correction), visual field examination, and tonometry with special attention to retinal 
abnormalities that are predisposing factors for RVO or CSR. Direct fundoscopy may be 
performed if indicated. Additional ophthalmic examinations (as detailed above) will be 
performed only as symptomatically warranted. In subjects with clinical suspicion of RVO or 
CSR, fluorescein angiography and/or optical coherence tomography are recommended.
If a clinically significant abnormal finding is observed, the investigator will record it as part of 
the subject’s medical history if it occurs prior to the start of study treatment on C1D1 and as an 
AE if it occurs after the commencement of study treatment.
9.4.7.
Clinical Laboratory Tests
Clinical laboratory assessments should be performed at screening and during the course of the 
study as outlined in the schedules of events (Section 9.4.9). All clinical laboratory tests will be 
performed at local laboratories. Specific tests that will be performed for hematology, serum 
chemistry, urinalysis, serology, and other tests are listed in Table 10. 
Table 10:
Clinical Laboratory Tests 
Hematology
Serum Chemistry
Urinalysisa
Serology
Other Tests
CBC
-Hemoglobin
-Hematocrit
-RBC counts
-WBC counts
-Platelet count
-WBC differentialb
 -Neutrophils
 -Eosinophils
 -Basophils
 -Lymphocytes
 -Monocytes
Albumin
Alkaline phosphatase
ALT
AST
BUN
Calcium
Chloride
CO2
Creatinine
Direct bilirubin
Gamma-GT
Glucose
Lactate dehydrogenase
Dipstick
-Specific gravity
-pH
-Protein
-Glucose
-Ketones
-Leukocyte esterase
-Blood
Pregnancy testc
Coagulation 
parameters
-PTT
-prothrombin time 
(or INR)
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Hematology
Serum Chemistry
Urinalysisa
Serology
Other Tests
Magnesium
Phosphorus 
Potassium
Sodium
Total bilirubin
Total cholesterol
Total protein
Uric acid
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CBC=complete blood count; 
CO2=carbon dioxide; eCRF=electronic case report form; GT=glutamyl transferase; INR=international normalized ratio; 
PTT=partial thromboplastin time; RBC=red blood cell; WBC=white blood cell.
a A microscopic examination is to be performed if indicated.
b Either manual or automated differential counts may be performed; if both are done, the manual counts will be entered into the 
eCRF.
c For women of child-bearing potential; either serum or urine pregnancy test may be performed. 
If a clinically significant abnormal finding is observed, the investigator will record it as part of 
the subject’s medical history if it occurs prior to the start of study treatment on C1D1 and as an 
AE if it occurs after the commencement of study treatment.
9.4.8.
Disease Assessments
CT or MRI scan (or other appropriate disease evaluation method, including tumor marker 
measurement, as applicable) will be performed as indicated in the schedules of events 
(Section 9.4.9) and Section 9.1. Lesion assessment must be done for chest, abdomen, pelvis, and 
any area of known disease. The same diagnostic method must be used throughout the study to 
evaluate each lesion.
9.4.9.
Schedules of Events
Table 11 presents the complete schedule of events for Regimen 1 Continuous Dosing, and 
Table 12 presents that for Regimen 2 Intermittent Dosing with details following in text. Table 13 
presents the Schedule of Events for the Study Extension phase. 
Clinical and diagnostic laboratory evaluations are detailed before study entry, throughout the 
study, and at the follow-up evaluation. The purpose of obtaining these detailed measurements is 
to ensure adequate assessments of preliminary clinical activity, safety, and tolerability. Repeat 
clinical evaluations and laboratory studies more frequently if clinically indicated.
Note any deviation from protocol procedures. Investigators are responsible for implementing 
appropriate measures to prevent the recurrence of violations and deviations and to report to their 
IRB/IEC according to policy.
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Table 11:
Schedule of Events Regimen 1 – Continuous (Days 1 Through 21) Dosing
Cycle (21 Days)a
1
2
≥3a
Tx 
Termb
30-day 
Safety 
FUc
Long-
term 
FU
Cycle Dayd
1e
2
8
15
1
2
8
15
1
Study treatment dispensation
x
x
x
x
x
x
x
Dosing compliance information
x
x
x
x
x
x
x
Procedures
Screeningf
Informed consent
x
Medical history
x
Investigator's confirmation of eligibility
x
x
PE/symptom-directed PEg
x
x
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
x
Vital signsh
x
x
x
x
x
x
x
x
x
x
x
x
ECOG performance status
x
x
x
x
x
x
x
x
x
x
12-lead ECGi
x
x
x
x
x
x
x
x
ECHO or MUGA scan
x
Repeat every 2 cycles for the first 4 cycles and then every 
4 cycles thereafter (±7 days)
x
Ophthalmic examinationj
x
Concomitant medications/AEsk
x
x
x
x
x
x
x
x
x
x
x
x
Randomization (if applicable), enrollment
x
Laboratory Assessments
Hematologyl,m
x
x
x
x
x
x
x
x
x
Coagulationm,n
x
x
x
x
x
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Cycle (21 Days)a
1
2
≥3a
Tx 
Termb
30-day 
Safety 
FUc
Long-
term 
FU
Cycle Dayd
1e
2
8
15
1
2
8
15
1
Chemistrym,o
x
x
x
x
x
x
x
x
x
Urinalysism,p
x
x
x
x
x
Serum or urine pregnancy testm,q
x
x
x
x
x
Pharmacokineticsr
x
x
x
xs
xt
Blood sample for ctDNAu
x
x
x
x
x
Blood (PBMC) sample for germline DNA
x
Obtain archival tumor tissuev
x
Collect pretreatment biopsyv
x
Collect on-treatment biopsyv
x
Disease Assessments
Response assessmentw
x
At the end of every 2 cycles (±7 days) for the first 4 cycles 
and then every 4 cycles (±1 cycle) thereafter
Health status follow-upx
Every 
3 months
AE=adverse event; CxDx=Cycle x Day x; CBC=complete blood count; ctDNA=circulating tumor DNA; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; eCRF=electronic case report form; FFPE=formalin-fixed paraffin embedded; FU=follow-up; INR=international normalized ratio; MRI=magnetic 
resonance imaging; MUGA=multiple-gated acquisition; PBMC=peripheral blood mononuclear cell; PE=physical examination; PK=pharmacokinetic; PTT= partial thromboplastin 
time; Tx Term=Treatment Termination.
a After Cycle 6, the specific visit schedule and assessments are at the investigator's discretion; at a minimum, information should be collected regarding concomitant medications, 
AEs, dosing compliance, and, at least once a month, pregnancy tests. Continue to collect efficacy and response assessments, in the manner described in the protocol, until disease 
progression (for response assessment) or death (for survival assessment), or the subject withdraws consent.
b Perform Tx Term visit procedures when a subject permanently discontinues study treatment, regardless of whether or not the subject plans to continue participating in the study 
(unless consent to continue study participation is withdrawn by the subject). The visit is to occur within 7 days after the last study treatment or within 3 days before starting new 
anticancer treatment and before the 30-day Safety Follow-up visit. If a subject discontinues study treatment at a scheduled visit, the assessments at that visit can be used to fulfill 
the Tx Term visit requirements.
c The 30-day Safety Follow-up visit must occur 30 (+5) days after the last dose of ASTX029 or within 3 days before starting new cancer treatment. 
d In Phase 1 starting with C2D8, study visits have a visit window of ±1 day. In Phase 2, all study visits for Cycles ≥2 have a visit window of ±2 days.
e On C1D1 (the first day of study treatment administration), complete the PE, vital signs, weight, and laboratory evaluations before administration of study treatment. Laboratory 
evaluations do not need to be repeated if screening tests are within 4 days prior to first dose of ASTX029. For subjects who had a full PE performed at screening within 4 days 
prior to the first dose of ASTX029, it is not necessary to repeat the full PE on C1D1; a symptom-directed PE on C1D1 can be done instead.
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f Screening procedures must occur within 21 days prior to first dose of ASTX029.
g At screening, a complete PE per the institutional standard practice, but including a skin examination (Section 9.4.1), will be performed. After screening, symptom-directed PEs 
will be performed at the time points indicated and at the investigator's discretion. 
h Obtain vital signs at screening; predose on Day 1 of each cycle and on C1D2, C1D8, C1D15, C2D2, C2D8, and C2D15; at the Tx Term visit; and at the Safety Follow-up visit. 
In addition, obtain systolic/diastolic blood pressure and heart rate at 1 hour (±30 minutes) postdose on C1D1 and C2D1. Assess all vital signs after the subject has rested in a 
sitting or semirecumbent position for at least 3 minutes.
i The 12-lead ECGs will be performed at screening and predose and 2 hours (±30 minutes) postdose on C1D1 and C2D1; they will be performed predose at all other time points 
on the dosing days and at the Tx Term visit as indicated. All ECGs will be recorded at 25 mm/second in triplicate, with each recording separated by at least 30 seconds, while the 
subject is in a semirecumbent position (Section 9.4.4). Two copies of the ECG tracing should be obtained at the time of the ECG; the first copy will be kept in the subject’s 
medical chart and the second copy will be kept in the study file for retrospective collection by the sponsor if necessary. On C1D1, ECG findings must meet study entry criteria 
before dosing.
j An ophthalmic examination will be performed at screening. Additional ophthalmic examinations will be performed only as symptomatically warranted. Refer to Section 9.4.6 for 
details. 
k Record all medications a subject takes starting from 14 days before study treatment initiation and ending 30 days after the last dose of study treatment. Record screening 
procedure-related AEs that occur before the start of study treatment and new AEs from the start of study treatment until 30 days after the last dose of study treatment or until the 
subject starts a new cancer treatment, including new investigational treatment, whichever occurs first. Also record screening procedure-related AEs that occur before the start of 
study treatment. Refer to Section 10.2. 
l Hematology must include CBC with either manual or automated differential and platelet counts; if both are done, the manual counts will be entered into the eCRF (Table 10). 
C1D1 hematology evaluations do not need to be repeated if screening tests are within 4 days prior to first dose of ASTX029. On C1D1, all hematology evaluations must meet 
study entry criteria before dosing. 
m Hematology, chemistry, coagulation, and urinalysis tests may be performed on the day before the visits and the pregnancy test may be performed within 24 hours before the start 
of study treatment Cycles 1-6 if more convenient.
n Collect PTT and prothrombin time (or INR) at screening, predose on Day 1 of each cycle, and at the Tx Term visit. The C1D1 coagulation evaluations do not need to be repeated 
if screening tests are done within 4 days prior to first dose of ASTX029. 
o Serum chemistry must include the analytes listed in Table 10. The C1D1 chemistry evaluations do not need to be repeated if screening tests are within 4 days prior to first dose 
of ASTX029. On C1D1, all chemistry evaluations must meet study entry criteria before dosing.
p Urinalysis includes dipstick test (if available) and microscopic examination (if indicated) (Table 10). The C1D1 urinalysis evaluations do not need to be repeated if screening 
tests are within 4 days prior to the first dose of ASTX029.
q Pregnancy test: to be performed at screening, within 24 hours before the start of Cycles 1 through 6, at least monthly during treatment thereafter, and at the Tx Term visit (only 
for women of child-bearing potential). 
r See Table 4 and Table 6, respectively (Section 9.2.1), for the complete PK blood draw schedule for Phase 1 and Phase 2.
s Collect PK blood samples in Phase 1 only; see Table 4.
t Collect PK blood samples in Phase 2 only; see Table 6.
u See Table 8 for the ctDNA sample collection schedule. On dosing days, predose samples are to be collected within 60 minutes prior to administration of study treatment.
v If archived tumor tissue (FFPE) is available, it will be requested for use in this study during screening. In addition, collection of fresh tumor biopsies is encouraged (optional) in 
Phase 1 Part A and Phase 2 and mandatory in Phase 1 Part B of the study during screening and on C2D8 (±1 day), 4 hours (±1 hour) postdose. See Table 9 for the biopsy 
collection schedule.
w CT or MRI scan (or other appropriate disease evaluation method, including tumor marker measurement, as applicable) will be performed at screening, at the end of every 2 
cycles (±7 days) for the first 4 cycles, and then every 4 cycles (±1 cycle) thereafter until clinical and/or radiographic disease progression, or death, or the subject withdraws 
consent, whichever occurs first (Section 9.1, Section 9.4.8). If the last assessment was >12 weeks prior to study treatment withdrawal and disease progression had not been 
documented, a disease assessment should be obtained at the Tx Term visit. 
x Beginning 3 months after discontinuation of treatment, subjects will be contacted by telephone for collection of health status information every 3 months until death, the subject 
withdraws consent, or end of study, whichever occurs first (Section 9.4.15).
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Table 12:
Schedule of Events Regimen 2 – Intermittent (Days 1 Through 14) Dosing
Cycle (21 Days)a
1
2
≥3a
Tx Termb
30-day 
Safety FUc
Long-
term FU
Cycle Dayd 
1e
2
8
14
15
1
8
15
1
Study treatment dispensation
x
x
x
x
x
Dosing compliance information
x
x
x
x
x
Procedures
Screeningf
Informed consent
x
Medical history
x
Investigator's confirmation of eligibility
x
x
PE/symptom-directed PEg
x
x
x
x
x
x
x
x
x
x
Height 
x
Weight
x
x
x
x
Vital signsh
x
x
x
x
x
x
x
x
x
x
x
x
ECOG performance status
x
x
x
x
x
x
x
x
x
x
12-lead ECGi
x
x
x
x
x
x
x
x
x
ECHO or MUGA scan
x
Repeat every 2 cycles for the first 4 cycles and 
then every 4 cycles thereafter (±7 days)
x
Ophthalmic examinationj
x
Concomitant medications/AEsk
x
x
x
x
x
x
x
x
x
x
x
x
Randomization (if applicable), enrollment
x
Laboratory Assessments 
Hematologyl,m
x
x
x
x
x
x
x
x
x
Coagulationm,n
x
x
x
x
x
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Cycle (21 Days)a
1
2
≥3a
Tx Termb
30-day 
Safety FUc
Long-
term FU
Cycle Dayd 
1e
2
8
14
15
1
8
15
1
Study treatment dispensation
x
x
x
x
x
Dosing compliance information
x
x
x
x
x
Procedures
Screeningf
Informed consent
x
Medical history
x
Investigator's confirmation of eligibility
x
x
PE/symptom-directed PEg
x
x
x
x
x
x
x
x
x
x
Chemistrym,o
x
x
x
x
x
x
x
x
x
Urinalysism,p
x
x
x
x
x
Serum or urine pregnancy testm,q
x
x
x
x
x
Pharmacokineticsr
x
x
x
x
xs
Blood sample for ctDNAt
x
x
x
x
x
Blood (PBMC) sample for germline DNA
x
Obtain archival tumor tissueu
x
Collect pretreatment biopsyu
x
Collect on-treatment biopsyu
x
Disease Assessments
Response assessmentv
x
At the end of every 2 cycles (±7 days) for the first 4 
cycles and then every 4 cycles (±1 cycle) thereafter
Health status follow-upw
Every 3 
months
AE=adverse event; CxDx=Cycle x Day x; CBC=complete blood count; ctDNA=circulating tumor DNA; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; eCRF=electronic case report form; FFPE=formalin-fixed paraffin embedded; FU=follow-up; INR=international normalized ratio; MRI=magnetic 
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resonance imaging; MUGA=multiple-gated acquisition; PBMC= peripheral blood mononuclear cell; PE=physical examination; PK=pharmacokinetic; PTT= partial thromboplastin 
time; Tx Term=Treatment Termination.
a After Cycle 6, the specific visit schedule and assessments are at the investigator's discretion; at a minimum, information should be collected regarding concomitant medications, 
AEs, dosing compliance, and, at least once a month, pregnancy tests. Continue to collect efficacy and response assessments, in the manner described in the protocol, until disease 
progression (for response assessment) or death (for survival assessment), or the subject withdraws consent.
b Perform Tx Term visit procedures when a subject permanently discontinues study treatment, regardless of whether or not the subject plans to continue participating in the study 
(unless consent to continue study participation is withdrawn by the subject). The visit is to occur within 7 days after the last study treatment or within 3 days before starting new 
anticancer treatment and before the 30-day Safety Follow-up visit. If a subject discontinues study treatment at a scheduled visit, the assessments at that visit can be used to fulfill 
the Tx Term visit requirements.
c The 30-day Safety Follow-up visit must occur 30 (+5) days after the last dose of ASTX029 or within 3 days before starting new cancer treatment. 
d In Phase 1 starting with C2D8, study visits have a visit window of ±1 day. In Phase 2, all study visits for Cycles ≥2 have a visit window of ±2 days.
e On C1D1 (the first day of study treatment administration), complete the PE, vital signs, weight, and laboratory evaluations before administration of study treatment. Laboratory 
evaluations do not need to be repeated if screening tests are within 4 days prior to first dose of ASTX029. For subjects who had a full PE performed at screening within 4 days 
prior to the first dose of ASTX029, it is not necessary to repeat the full PE on C1D1; a symptom-directed PE on C1D1 can be done instead. 
f Screening procedures must occur within 21 days prior to first dose of ASTX029.
g At screening, a complete PE per the institutional standard practice, but including a skin examination, (Section 9.4.1) will be performed. After screening, symptom-directed PEs 
will be performed at the time points indicated and at the investigator's discretion. 
h Obtain vital signs at screening; predose on Day 1 of each cycle and on C1D2, C1D8, C1D14, and C2D8; on C1D15 and C2D15; at the Tx Term visit; and at the Safety Follow-
up visit. In addition, obtain systolic/diastolic blood pressure and resting heart rate at 1 hour (±30 minutes) postdose on C1D1 and C1D14. Assess all vital signs after the subject 
has rested in a sitting or semirecumbent position for at least 3 minutes.
i The 12-lead ECGs will be performed at screening and predose and 2 hours (±30 minutes) postdose on C1D1 and C1D14; they will be performed predose at all other time points 
on the dosing days and at the Tx Term visit as indicated. All ECGs will be recorded at 25 mm/second in triplicate, with each recording separated by at least 30 seconds, while the 
subject is in a semirecumbent position (Section 9.4.4). Two copies of the ECG tracing should be obtained at the time of the ECG; the first copy will be kept in the subject’s 
medical chart and the second copy will be kept in the study file for retrospective collection by the sponsor if necessary. On C1D1, ECG findings must meet study entry criteria 
before dosing.
j An ophthalmic examination will be performed at screening. Additional ophthalmic examinations will be performed only as symptomatically warranted. Refer to Section 9.4.6 for 
details. 
k Record all medications a subject takes starting from 14 days before study treatment initiation and ending 30 days after the last dose of study treatment. Record screening 
procedure-related AEs that occur before the start of study treatment and new AEs from the start of study treatment until 30 days after the last dose of study treatment or until the 
subject starts new cancer treatment, including new investigational treatment, whichever occurs first. Also record screening procedure-related AEs that occur before the start of 
study treatment. Refer to Section 10.2. 
l Hematology must include CBC with either manual or automated differential and platelet counts; if both are done, the manual counts will be entered into the eCRF (Table 10). 
C1D1 hematology evaluations do not need to be repeated if screening tests are within 4 days prior to first dose of ASTX029. On C1D1, all hematology evaluations must meet 
study entry criteria before dosing. 
m Hematology, chemistry, coagulation, and urinalysis tests may be performed on the day before the visits and the pregnancy tests may be performed within 24 hours before the 
start of study treatment Cycles 1-6 if more convenient.
n Collect PTT and prothrombin time (or INR) at screening, predose on Day 1 of each cycle, and at the Tx Term visit. The C1D1 coagulation evaluations do not need to be repeated 
if screening tests are done within 4 days prior to first dose of ASTX029. 
o Serum chemistry must include the analytes listed in Table 10. The C1D1 chemistry evaluations do not need to be repeated if screening tests are within 4 days prior to first dose 
of ASTX029. On C1D1, all chemistry evaluations must meet study entry criteria before dosing. 
p Urinalysis includes dipstick test (if available) and microscopic examination (if indicated) (Table 10). The C1D1 urinalysis evaluations do not need to be repeated if screening 
tests are within 4 days of first dose of ASTX029.
q Pregnancy test: to be performed at screening, within 24 hours before the start of Cycles 1 through 6, at least monthly during treatment thereafter, and at the Tx Term visit (only 
for women of child-bearing potential).
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r See Table 5 and Table 7, respectively (Section 9.2.1), for the complete PK blood draw schedule for Phase 1 and Phase 2.
s Collect PK blood samples in Phase 2 only; see Table 7.
t See Table 8 for the ctDNA sample collection schedule. On dosing days, predose samples are to be collected within 60 minutes prior to administration of study treatment.
u If archived tumor tissue (FFPE) is available, it will be requested for use in this study during screening. In addition, collection of fresh tumor biopsies is encouraged (optional) in 
Phase 1 Part A and Phase 2 and mandatory in Phase 1 Part B of the study during screening and on C2D8 (±1 day), 4 hours (±1 hour) postdose. See Table 9 for the biopsy 
collection schedule.
v CT or MRI scan (or other appropriate disease evaluation method, including tumor marker measurement, as applicable) will be performed at screening, at the end of every 2 
cycles (±7 days) for the first 4 cycles, and then every 4 cycles (±1 cycle) thereafter until clinical and/or radiographic disease progression, or death, or the subject withdraws 
consent, whichever occurs first (Section 9.1, Section 9.4.8. If the last assessment was >12 weeks prior to study treatment withdrawal and disease progression had not been 
documented, a disease assessment should be obtained at the Treatment Termination visit. 
w Beginning 3 months after discontinuation of treatment, subjects will be contacted by telephone for collection of health status information every 3 months until death, the subject 
withdraws consent, or end of study, whichever occurs first (Section 9.4.15).
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Table 13
Schedule of Events – Study Extension Phase
Treatment Period 
(1 cycle = 21 days)
Safety Follow-Up
Notes
At Least Every 3 Cycles
30 (+5 days) 
After Last Dose
Physical examination
X
X
Only symptom-directed examinations required
Vital signs
X
X
Assess all vital signs after the subject has rested in a sitting or 
semirecumbent position for at least 3 minutes.
Weight
X
X
Ophthalmological 
examination
(X)
(X)
Performed only as symptomatically warranted. Section 9.4.6 
ECOG performance status
X
X
See Appendix 1
12-Lead electrocardiogram 
X
X
Performed in triplicate, with each recording separated by at 
least 30 seconds. See Section 9.4.4.
Hematology 
X
X
Must include CBC with either manual or automated 
differential and platelet counts. See Table 10
Coagulation
X
X
Includes PTT and prothrombin time (or INR). See Table 10
Chemistry 
X
X
See Table 10
Pregnancy test
X
X
If applicable. Additional testing (urine or serum) as required 
per local practice.
Concomitant medications/ 
AEs
X
X
Collect through 30 days after administration of the last dose 
of study treatment or until the subject starts of new cancer 
treatment, whichever occurs first.  See Section 7.6 and 
Section 9.3 
Response assessment 
(CT/MRI)
X
Tumor assessments may be performed as necessary to 
determine continued benefit from treatment, every 4 cycles 
(± 1 cycle), or as clinically indicated, until radiologic PD or 
initiation of new anticancer therapy (whichever occurs first). 
See Section 9.4.8 
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AE=adverse event; ECOG=Eastern Cooperative Oncology Group
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9.4.10.
Screening and Baseline Procedures 
After the investigator or sub-investigator confirms that a subject is eligible and willing to 
participate in the study, study center personnel will forward the appropriate documentation to the 
attention of the sponsor or sponsor delegate according to the study regulatory binder. 
Within 21 days before treatment administration, perform the following study procedures and 
tests:

Written informed consent. The ICF must be signed and dated by the subjects before 
any study-specific samples are collected or study-specific procedures are initiated. 

Complete medical history, including demographics. Record disease history, including 
the date of initial diagnosis and list prior treatments and responses to these 
treatments). Document concurrent medical signs and symptoms to establish baseline 
conditions.

Complete PE per the institutional standard practice, but including a skin examination, 
and including height and weight. 

Vital signs include resting systolic/diastolic blood pressure, resting respiration rate, 
resting heart rate, and body temperature. Assess vital signs after the subject has rested 
in a sitting or semirecumbent position for at least 3 minutes (Section 9.4.2).

ECOG performance status assessment (Appendix 1). 

12-lead ECG in triplicate (Section 9.4.4).

ECHO or MUGA scan.

Ophthalmic examination (Section 9.4.6).

Record screening procedure-related AEs that occur before the start of study treatment 
and concomitant medications starting 14 days before study treatment initiation.

Sample collection for clinical laboratory tests (hematology, coagulation, serum 
chemistry, and urinalysis) (Table 10). 

Serum or urine pregnancy test: for women of child-bearing potential only. Results 
must be negative for the subject to be eligible for enrollment into the study.

Blood sample collection for ctDNA and blood (PBMC) sample collection for 
germline DNA (Section 9.2.2, Table 8).

Archival tumor tissue (FFPE) collection (Section 9.2.2, Table 9).

Pretreatment fresh tumor biopsy collection (optional in Phase 1 Part A and Phase 2 
and mandatory in Phase 1 Part B) (Section 9.2.2, Table 9).

CT or MRI scan (or other appropriate disease evaluation method, including tumor 
marker measurement, as applicable).

Investigator's confirmation of eligibility. Perform all necessary procedures and 
evaluations to document that the subject meets each eligibility criterion.
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
Randomize patient (Phase 1, if applicable).

Enroll patient.
9.4.11.
Treatment and Follow-up Procedures
The first day of study drug administration is C1D1. Consecutive QD oral doses of study drug 
will be administered (or self-administered) on Days 1 to 21 (Regimen 1) or Days 1 to 14 
(Regimen 2). For details on study drug administration please refer to Section 7.1.7. Subjects 
should drink 1 full glass of water immediately after drug ingestion and not lay down for at least 
30 minutes after drug ingestion. On scheduled visit days, subjects should wait to take the study 
drug until after they have checked into the study center and undergone the predose procedures. 
Subjects should record the time and date of each dose they self-administer in their dosing diary.
Treatment and follow-up procedures will be followed for Regimen 1 or 2, based on the regimen 
selected.
9.4.11.1.
Cycle 1 – Week 1
Week 1 is a dosing week in both Regimen 1 and Regimen 2: consecutive QD oral doses of study 
treatment will be administered (or self-administered) on Days 1 to 7.
9.4.11.1.1. Cycle 1 – Week 1 – Day 1
Before administration of study treatment:

Perform symptom-directed PE (Section 9.4.1).

Record subject's weight.

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Perform predose 12-lead ECG in triplicate (Section 9.4.4). Note: ECG findings must 
meet study entry criteria before dosing.

Record screening procedure-related AEs that occur before the start of study treatment 
and concomitant medications received since screening.

Collect blood samples for hematology, coagulation, and serum chemistry laboratory 
tests and review results; collect urine sample for urinalysis (Table 10). Note: 
hematology and chemistry values must meet study entry criteria before dosing, C1D1 
hematology, coagulation, serum chemistry, and urine evaluations do not need to be 
repeated if screening tests are done within 4 days prior to first dose of ASTX029, and 
these tests may be performed on the day before the visit if more convenient.

Perform serum or urine pregnancy test for women of child-bearing potential only, and 
this test may be performed within 24 hours before the start of study treatment if more 
convenient.

Collect predose blood sample for PK analysis (Section 9.2.1, Table 4, Table 5, 
Table 6, and Table 7).
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
Collect predose blood sample for ctDNA (Section 9.2.2, Table 8).

Confirm eligibility.
Subject ingests study treatment while at the clinic.
After administration of study treatment:

Record blood pressure and heart rate 1 hour (±30 minutes) postdose (Section 9.4.2).

Perform 12-lead ECG in triplicate 2 hours (±30 minutes) postdose (Section 9.4.4).

Record AEs and concomitant medications.

Collect blood samples for postdose PK analysis (Section 9.2.1, Table 4, Table 5, 
Table 6, and Table 7).

Dispense study treatment (ASTX029), provide instruction for self-administration, and 
instruct subject to, on dosing days when there is a scheduled visit, refrain from 
ingesting the study drug until after being on-site at the study clinic and the predose 
study procedures have been performed.

Provide a dosing diary to the subject and instructions for how to enter dosing 
information.
9.4.11.1.2. Cycle 1 – Week 1 – Day 2
Before administration of study treatment:

Record vital signs (Section 9.4.2).

Perform predose 12-lead ECG in triplicate (Section 9.4.4).

Record AEs and concomitant medications.

Collect post C1D1 dose blood sample for PK analysis (Section 9.2.1, Table 4, 
Table 5, Table 6, and Table 7).
Subject ingests study treatment while at the clinic.
After administration of study treatment:

Record AEs and concomitant medications.
9.4.11.2.
Cycle 1 – Week 2 – Day 8 
Week 2 is a dosing week in both Regimen 1 and Regimen 2: consecutive QD oral doses of study 
treatment will be administered (or self-administered) on Days 8 to 14.
Before administration of study treatment (note: hematology and serum chemistry tests may be 
performed on the day before the visit if more convenient):

Perform symptom-directed PE (Section 9.4.1).

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 
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
Record AEs and concomitant medications.

Perform predose 12-lead ECG in triplicate (Section 9.4.4).

Collect blood samples for hematology and serum chemistry laboratory tests 
(Table 10).
Subject ingests study treatment while at the clinic.
After administration of study treatment:

Record AEs and concomitant medications.

Review dosing diary to assess dosing compliance.

Dispense study treatment (ASTX029), provide instruction for self-administration as 
needed, and instruct subject to, on dosing days when there is a scheduled visit, refrain 
from ingesting the study drug until after being are on-site at the study clinic and the 
predose study procedures have been performed.
9.4.11.3.
Cycle 1 – Week 2 – Day 14 Regimen 2 Only
Week 2 Day 14 is the last day of dosing in Regimen 2.
For subjects receiving Regimen 2 treatment (before administration of study treatment) (note: 
hematology and serum chemistry tests may be performed on the day before the visit if more 
convenient):

Perform symptom-directed PE (Section 9.4.1).

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Perform predose 12-lead ECG in triplicate (Section 9.4.4).

Record AEs and concomitant medications.

Review dosing diary to assess dosing compliance. 

Collect blood samples for hematology and serum chemistry laboratory tests 
(Table 10). 

Collect predose blood sample for PK analysis (Section 9.2.1, Table 5 and Table 7).
Subject ingests study treatment while at the clinic.
For subjects receiving Regimen 2 treatment (after administration of study treatment):

Record blood pressure and heart rate 1 hour (±30 minutes) postdose (Section 9.4.2).

Perform 12-lead ECG in triplicate 2 hours (±30 minutes) postdose (Section 9.4.4).

Record AEs and concomitant medications.

Collect postdose blood samples for PK analysis (Section 9.2.1, Table 5 and Table 7).
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9.4.11.4.
Cycle 1 – Week 3 – Day 15
Week 3 is a dosing week in Regimen 1 (only): consecutive QD oral doses of study treatment will 
be administered (or self-administered) on Days 15 to 21.
For subjects receiving Regimen 1 treatment (before administration of study treatment) (note: 
hematology and serum chemistry tests may be performed on the day before the visit if more 
convenient):

Perform symptom-directed PE (Section 9.4.1).

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Record AEs and concomitant medications.

Perform predose 12-lead ECG in triplicate (Section 9.4.4).

Collect blood samples for hematology and serum chemistry laboratory tests 
(Table 10). 
Subject receiving Regimen 1 treatment ingests study treatment while at the clinic.
After administration of study treatment for subjects receiving Regimen 1 treatment:

Record AEs and concomitant medications.

Review dosing diary to assess dosing compliance.

Dispense study treatment (ASTX029), provide instruction for self-administration as 
needed, and instruct subject to, on dosing days when there is a scheduled visit, refrain 
from ingesting the study drug until after being are on-site at the study clinic and the 
predose study procedures have been performed. 
For subjects receiving Regimen 2 treatment:

Record vital signs (Section 9.4.2).

Record AEs and concomitant medications.

Perform 12-lead ECG in triplicate (Section 9.4.4).

Collect post C1D14 dose blood sample for PK analysis (Section 9.2.1, Table 5 and 
Table 7).
9.4.11.5.
Cycle 2 – Week 1
Week 1 is a dosing week in both Regimen 1 and Regimen 2: consecutive QD oral doses of study 
treatment will be administered (or self-administered) on Days 1 to 7.
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9.4.11.5.1. Cycle 2 – Week 1 – Day 1
Before administration of study treatment (note: hematology, serum chemistry, coagulation, and 
urinalysis tests may be performed on the day before the visit and the pregnancy test may be 
performed within 24 hours before administration of study treatment if more convenient):

Perform symptom-directed PE (Section 9.4.1).

Record subject's weight.

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Perform predose 12-lead ECG in triplicate (Section 9.4.4).

Record AEs and concomitant medications.

Collect blood samples for hematology, coagulation, and serum chemistry laboratory 
tests and review results; collect urine sample for urinalysis (Table 10). 

Perform serum or urine pregnancy test for women of child-bearing potential only.

Collect predose blood sample for ctDNA (Section 9.2.2, Table 8).
In addition, for subjects receiving Regimen 1 treatment (before administration of study 
treatment):

Collect predose blood sample for PK analysis (Section 9.2.1, Table 4 and Table 6).
Subject ingests study treatment while at the clinic. 
After administration of study treatment:

Record AEs and concomitant medications.

Dispense study treatment (ASTX029), provide instruction for self-administration as 
needed, and instruct subject to, on dosing days when there is a scheduled visit, refrain 
from ingesting the study drug until after being are on-site at the study clinic and the 
predose study procedures have been performed.

Provide a dosing diary to the subject and instructions for how to enter dosing 
information.
In addition, for subjects receiving Regimen 1 treatment (after administration of study treatment):

Review dosing diary to assess dosing compliance.

Record blood pressure and heart rate 1 hour (±30 minutes) postdose (Section 9.4.2).

Perform 12-lead ECG in triplicate 2 hours (±30 minutes) postdose (Section 9.4.4).

Collect postdose blood samples for PK analysis (Section 9.2.1, Table 4 and Table 6).
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9.4.11.5.2. Cycle 2 – Week 1 – Day 2 Regimen 1 Only
For subjects receiving Regimen 1 treatment (Before administration of study treatment):

Record vital signs (Section 9.4.2).

Record AEs and concomitant medications.
For subjects in Phase 1 receiving Regimen 1 treatment (before administration of study 
treatment):

Collect post C2D1 blood sample for PK analysis (Section 9.2.1, Table 4).
Subject ingests study treatment while at the clinic.
For subjects receiving Regimen 1 treatment (After administration of study treatment):

Record AEs and concomitant medications. 
9.4.11.6.
Cycle 2 – Week 2 – Day 8 
Week 2 is a dosing week in both Regimens 1 and 2: consecutive QD oral doses of study 
treatment will be administered (or self-administered) on Days 8 to 14.
Before administration of study treatment (note: hematology and serum chemistry tests may be 
performed on the day before the visit if more convenient):

Perform symptom-directed PE (Section 9.4.1).

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Record AEs and concomitant medications.

Collect blood samples for hematology and serum chemistry laboratory tests 
(Table 10).
Subject ingests study treatment while at the clinic.
After administration of study treatment:

Record AEs and concomitant medications.

Collect fresh tumor biopsy (optional in Phase 1 Part A and Phase 2 and mandatory in 
Phase 1 Part B) 4 hours (±1 hour) postdose (Section 9.2.2, Table 9).

Dispense study treatment (ASTX029), provide instruction for self-administration as 
needed, and instruct subject to, on dosing days when there is a scheduled visit, refrain 
from ingesting the study drug until after being are on-site at the study clinic and the 
predose study procedures have been performed. 

Review dosing diary to assess dosing compliance.
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9.4.11.7.
Cycle 2 – Week 3 – Day 15
Week 3 is a dosing week in Regimen 1 (only): consecutive QD oral doses of study treatment will 
be administered (or self-administered) on Days 15 to 21.
For subjects receiving Regimen 1 treatment (before administration of study treatment) (note: 
hematology and serum chemistry tests may be performed on the day before the visit if more 
convenient):

Perform symptom-directed PE (Section 9.4.1).

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Record AEs and concomitant medications.

Collect blood samples for hematology and serum chemistry laboratory tests 
(Table 10).
Subject receiving Regimen 1 treatment ingests study treatment while at the clinic.
After administration of study treatment for subjects receiving Regimen 1 treatment:

Record AEs and concomitant medications.

Dispense study treatment (ASTX029), provide instruction for self-administration as 
needed, and instruct subject to, on dosing days when there is a scheduled visit, refrain 
from ingesting the study drug until after being are on-site at the study clinic and the 
predose study procedures have been performed. 

Review dosing diary to assess dosing compliance.
For subjects receiving Regimen 2 treatment (note: hematology and serum chemistry tests may be 
performed on the day before the visit if more convenient):

Perform symptom-directed PE (Section 9.4.1).

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Record AEs and concomitant medications.

Collect blood samples for hematology and serum chemistry laboratory tests 
(Table 10). 
9.4.11.8.
Cycle 2 End of Cycle (before Cycle 3 Day 1)

Assess subject’s disease by CT or MRI scan (or other appropriate disease evaluation 
method, including tumor marker measurement, as applicable).
9.4.11.9.
Cycles 3 Through 6 – Week 1 – Day 1
Week 1 is a dosing week in both Regimens 1 and 2: consecutive QD oral doses of study 
treatment will be administered (or self-administered) on Days 1 to 7.
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Before administration of study treatment (note: hematology, serum chemistry, coagulation, and 
urinalysis tests may be performed on the day before the visits and the pregnancy tests may be 
performed within 24 hours before administration of study treatment Cycles 3 through 6 if more 
convenient):

Perform symptom-directed PE (Section 9.4.1).

Record subject's weight.

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Perform predose 12-lead ECG in triplicate (Section 9.4.4).

Record AEs and concomitant medications.

Collect blood samples for hematology, coagulation, and serum chemistry laboratory 
tests; collect urine sample for urinalysis (Table 10). 

Perform serum or urine pregnancy test for women of child-bearing potential only.

Collect predose blood sample for ctDNA (Section 9.2.2, Table 8).
Before administration of study treatment for subjects in Phase 2: 

Collect predose blood sample for PK analysis for Cycle 3 only (Section 9.2.1, Table 6 
and Table 7).
Subject ingests study treatment while at the clinic.
After administration of study treatment:

Record AEs and concomitant medications.

Review dosing diary to assess dosing compliance.

Dispense study treatment (ASTX029), provide instruction for self-administration as 
needed, and instruct subject to, on dosing days when there is a scheduled visit, refrain 
from ingesting the study drug until after being are on-site at the study clinic and the 
predose study procedures have been performed.

Provide a dosing diary to the subject and instructions for how to enter dosing 
information.
After administration of study treatment for subjects in Phase 2: 

Collect postdose blood samples for PK analysis for Cycle 3 only (Section 9.2.1, 
Table 6 and Table 7). 
9.4.11.10. Cycles 3 Through 6 – Week 2 – Day 8 
Week 2 is a dosing week in both Regimens 1 and 2: consecutive QD oral doses of study 
treatment will be administered (or self-administered) on Days 8 to 14.
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9.4.11.11. Cycle 3 Through 6 – Week 3 – Day 15
Week 3 is a dosing week in Regimen 1 (only): consecutive QD oral doses of study treatment will 
be administered (or self-administered) on Days 15 to 21.
9.4.11.12. End of Cycle 4 and at End of Every 4 Cycles (±1 Cycle) After Cycle 4 (Before 
Day 1 of Cycle 5 and Before Day 1 of Every 4 Cycles [±1 Cycle] After Cycle 5)

Assess subject’s disease by CT or MRI scan (or other appropriate disease evaluation 
method, including tumor marker measurement, as applicable).
9.4.12.
Cycle 7 and Subsequent Cycles 
After Cycle 6, the specific visit schedule and assessments are at the investigator's discretion; at a 
minimum, information should be collected regarding concomitant medications, AEs, dosing 
compliance, and, at least once a month, pregnancy tests. Continue to collect efficacy and 
response assessments, in the manner described in the protocol, until disease progression (for 
response assessment) or death (for survival assessment), or the subject withdraws consent.
9.4.13.
Treatment Termination Visit
This visit should occur within 7 days after the last study treatment or within 3 days before 
starting new cancer treatment and before the 30-day Safety Follow-up visit. (Note: hematology, 
serum chemistry, coagulation, urinalysis, and pregnancy tests may be performed on the day 
before the visit if more convenient.) If a subject discontinues study treatment at a scheduled visit, 
the assessments at that visit can be used to fulfill the Tx Term visit requirements. 
The visit should occur when a subject permanently discontinues study treatment, regardless of 
whether or not the subject plans to continue participating in the study, for long term follow up of 
health status (unless consent to continue study participation is withdrawn by the subject).

Perform symptom-directed PE (Section 9.4.1).

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Perform 12-lead ECG in triplicate (Section 9.4.4).

Perform ECHO or MUGA scan.

Record AEs and concomitant medications.

Collect blood samples for hematology, coagulation, and serum chemistry laboratory 
tests; collect urine sample for urinalysis (Table 10). 

Perform serum or urine pregnancy test for women of child-bearing potential only. 

Collect blood sample for ctDNA (Section 9.2.2, Table 8).

Review dosing diary to assess dosing compliance.

If the last disease assessment was >12 weeks prior to study treatment withdrawal and 
disease progression had not been documented, assess subject’s disease by CT or MRI 
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scan (or other appropriate disease evaluation method, including tumor marker 
measurement, as applicable).
9.4.14.
30-day Safety Follow-up Visit
This visit must occur 30 (±5) days after the last dose of study treatment or within 3 days before 
starting a new cancer treatment.

Perform symptom-directed PE (Section 9.4.1).

Record vital signs (Section 9.4.2).

Evaluate ECOG performance status (Appendix 1). 

Record AEs and concomitant medications.
9.4.15.
Long-Term Follow-up of Health Status
For subjects who remain on study, beginning 3 months after the discontinuation of study 
treatment, the subject's health status will be collected by telephone every 3 months until death, or 
the subject withdraws consent, or until the end of the study, whichever occurs first. The 
following health information will be collected and recorded in the source documents and eCRF:

Survival information.

Date of disease progression if subject did not have disease progression at the time 
they discontinued study treatment.
9.5.
Missed Evaluations
Evaluations should occur within the visit window specified by the protocol. If an evaluation is 
missed, reschedule and perform it as close as possible to the original date. If rescheduling 
becomes, in the investigator's opinion, medically unnecessary because the evaluation would 
occur too close to the next scheduled evaluation, it may be omitted.
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10.
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS
10.1.
Definitions
10.1.1.
Adverse Event (AE)
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant abnormal finding in laboratory tests or other diagnostic 
procedures), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality. An AE can arise from any use of the drug and from any route of 
administration, formulation, or dose, including an overdose. 
Disease progression is not considered to be an AE or SAE. If there are specific AEs that are 
always part of disease progression, these do not need to be reported as AEs or SAEs. Pre-existing 
medical conditions (other than natural progression of the disease being studied) judged by the 
investigator or subject to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period will be reported as AEs or SAEs as appropriate.
An AE or SAE can also be a complication that occurs as a result of protocol mandated 
procedures (eg, invasive procedures such as biopsies).
10.1.2.
Serious Adverse Events (SAEs)
An AE is considered serious, if in the view of either the investigator or sponsor, it results in any 
of the following outcomes:

Death.

A life-threatening AE.
An AE is considered "life-threatening" if in the view of either the investigator, or sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.

Inpatient hospitalization or prolongation of an existing hospitalization. 

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered serious when, based on the appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAE. Examples of such medical events are intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization; or development of drug dependency or drug abuse.
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10.2.
Adverse Event Reporting and Descriptions
Record new AEs from the start of study treatment until 30 days after the last dose of study 
treatment or until the subject starts new anticancer treatment, including new investigational 
treatment, whichever occurs first. Also record screening procedure-related AEs that occur before 
the start of study treatment. Collection of AEs may also continue until the decision is made to 
permanently discontinue study treatment.
Record all AEs either observed by the investigator or one of the medical collaborators, or 
reported by the subject spontaneously, or in response to the direct question below, in the AEs 
section of the subject's eCRF, in the source document, and if applicable, record on the SAE 
Report form. Whenever possible, the investigator should group signs and symptoms (including 
laboratory tests or other results of diagnostic procedures) into a single diagnosis under a single 
term. For example, cough, rhinitis, and sneezing might be reported as "upper respiratory 
infection" or a pulmonary infiltrate, positive sputum culture and fever might be reported as 
"pneumonia."
To optimize consistency of AE reporting across centers, ask the subject a standard, general, 
non-leading question to elicit any AEs (such as "Have you had any new symptoms, injuries, 
illnesses since your last visit?"). 
Death is an outcome of an SAE and usually not itself an SAE, unless it is death with no 
identifiable cause or event. In all other cases, record the cause of death as the SAE. Investigators 
will assess the status of previously reported, and occurrence of new AEs and SAEs at all subject 
evaluation time points during the study.
10.2.1.
Severity
Use the definitions found in the CTCAE v4.03 for grading the severity (intensity) of AEs. The 
CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each 
referenced AE and provides guidance not listed. Should a subject experience any AE not listed in 
the CTCAE v4.03, use the following grading system to assess severity:

Grade 1 – Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.

Grade 2 – Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL), such as preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc.

Grade 3 – Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL, such as bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.

Grade 4 – Life-threatening consequences; urgent intervention indicated.

Grade 5 – Death related to AE.
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10.2.2.
Relationship to Study Treatment (Suspected Adverse Reactions)
Assess all AEs/SAEs for relationship to study treatment or if applicable, to study procedure.
If an AE/SAE occurs before the first dose of study treatment, report it only if it is considered 
related to a study-specific procedure (eg, bleeding or local infection after skin punch biopsy). 
Those events will be recorded in the study database but will not be part of the 
treatment-emergent AE analysis. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
general guideline shown below. 
Related 
(Suspected Adverse 
Reaction)
A suspected adverse reaction means any AE for which there is a 
reasonable possibility that the drug caused the AE. Reasonable 
possibility means there is evidence to suggest a causal relationship 
between the drug and the AE such as a plausible temporal 
relationship between the onset of the AE and administration of the 
drug; and/or the AE follows a known pattern of response to the 
drug; and/or the AE abates or resolves upon discontinuation of the 
drug or dose reduction and, if applicable, reappears upon 
rechallenge. Further examples of type of evidence that would 
suggest a causal relationship between the drug and the AE:

A single occurrence of an event that is uncommon and 
known to be strongly associated with drug exposure (eg, 
angioedema, hepatic injury, Stevens-Johnson 
Syndrome),

One or more occurrences of an event that is not 
commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the 
drug (eg, acute myocardial infarction in a young 
woman),

An aggregate analysis of specific events observed in a 
clinical study (such as known consequences of the 
underlying disease or condition under investigation or 
other events that commonly occur in the study 
population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group.
Not Related 
(Not Suspected)
Adverse events that do not meet the definition above.
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10.2.3.
Reporting Requirements for Pregnancy and Abortion 
Report any pregnancy that occurs in a subject or male subject's female partner during the time 
between the first study-specific procedure and 90 days after the last dose of study treatment. 
Record any occurrence of pregnancy on the Pregnancy Report Form Part I and email it to the 
Sponsor’s Pharmacovigilance group or designee within 24 hours of learning of the event. After 
the birth of the baby, collect and report additional information on the baby until the baby is 
1 year old by completing the Pregnancy Report Form Part II. 
Sponsor’s Pharmacovigilance Group Contact Information
PRIMARY CONTACT: email 
DrugSafety@taihooncology.com
A subject must immediately inform the investigator if the subject or subject's partner becomes 
pregnant during the time between the first study-specific procedure and 90 days after the last 
dose of study treatment. Any female subjects receiving ASTX029 who become pregnant must 
immediately discontinue study treatment. The investigator should counsel the subject, discussing 
any risks of continuing the pregnancy and any possible effects on the fetus.
Report any abortion and the reason for it, whether therapeutic, elective or spontaneous, to the 
Sponsor’s Pharmacovigilance group or designee within 24 hours of learning of the event, 
through the SAE reporting process (Section 10.2.4).
10.2.4.
Reporting Requirements for Serious Adverse Events (SAEs)
All SAEs regardless of causality will be reported by the investigator to the Sponsor through the 
30-day period after the last dose of study treatment. Deaths and SAEs occurring after the 30-day 
safety follow-up period AND considered related to study treatment or study procedures must 
also be reported until the end of the study or subject death.
Report all SAEs (initial and follow-up information) on the SAE Report form and email it to the 
Sponsor’s Pharmacovigilance group or designee, within 24 hours of learning of the event or 
information (see below). The Sponsor may request follow-up and other additional information 
from the investigator (eg, hospital admission or discharge notes, laboratory results).
Sponsor’s Pharmacovigilance Group Contact Information
PRIMARY CONTACT: email 
DrugSafety@taihooncology.com
Report all deaths with the primary cause of death as the SAE term, as death is the outcome of the 
event, not the event itself. If an autopsy was performed, report the primary cause of death on the 
autopsy report as the SAE term. Forward autopsy and postmortem reports to the Sponsor’s 
Pharmacovigilance group or designee, as outlined above.
If study treatment is discontinued, temporarily suspended, or dose reduced because of an SAE, 
include this information in the SAE Report form.
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that qualify for 
mandatory expedited safety reporting to regulatory authorities where the SAE is suspected to be 
caused by the study treatment and is considered unexpected (ie, not listed as expected in the 
Reference Safety Information section of the current IB, clinical study protocol, or approved 
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labeling for marketed drugs). In this case, the Sponsor’s Pharmacovigilance group or designee 
will report to the relevant regulatory authorities and forward a formal notification describing the 
SUSAR to investigators, according to regulatory requirements. Each investigator must then 
notify his or her IRB/IEC of the SUSAR as required by local regulatory authorities and in 
accordance with IRB/IEC policy.
10.3.
Follow-up for Adverse Events
Follow all AEs and SAEs that are encountered during the protocol-specified AE reporting period 
(1) to resolution, (2) until the investigator assesses the subject as stable and the event is 
following a clinically expected outcome, or (3) until the subject is lost to follow-up or withdraws 
consent.
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11.
STATISTICS
Statistical analyses will be performed by the Sponsor or its designee.
Data summaries and listings will be generated using SAS version 9.4 or a more recent version 
(SAS Institute Inc., Cary, NC, USA).
The statistical analysis plan and/or the clinical study report will provide additional details of the 
analysis, which may include details of missing and, if applicable, unused data, as well as 
additional sensitivity analyses of the primary and secondary variables. The clinical study report 
will describe deviations from the statistical analysis plan, if any.
11.1.
Sample Size
The dose-escalation part of the study (Phase 1 Part A) follows a standard 3+3 study design, with 
a cohort size of 3 or 6 evaluable subjects. Dose escalation will continue until the MTD for each 
regimen evaluated is determined. Evaluable subjects for dose-escalation decisions in Part A are 
those who have completed the first cycle and have received at least 85% of planned doses in the 
first cycle of treatment (or were not able to receive at least 85% of planned doses due to safety 
concerns).
For Part B (of Phase 1), a sample size of 14 evaluable subjects will ensure a 90% probability of 
observing at least 1 adverse reaction to treatment for any adverse reaction with a ≥15% 
incidence. Evaluable subjects for Part B are all subjects who receive any amount of study drug.
For Phase 2, the sample size is based on a Simon’s Optimal 2-stage design (Simon 1989). Each 
cohort will enroll 10 subjects into the first stage. Should ≥2 first-stage subjects respond, an 
additional 19 subjects will be enrolled into the second stage. Therefore, up to 29 subjects will be 
used for each treatment cohort. The sample size, (10+19) 29, under this Simon’s Optimal 2-stage 
design, will achieve a power of 80% to test the null hypothesis of ORR p0 ≤0.1 at a 1-sided alpha 
of 0.05 assuming the response rate p1 is 0.3. For Stage 2, the null hypothesis will be rejected if 
≥6 responses are observed in a cohort of 29 subjects. For Cohort F (which will enroll patients 
with various tumor types and gene aberrations [Table 2]), the sponsor, with approval of the 
DSRC, may expand enrollment for a particular molecularly defined subpopulation in which the 
most number of responses are observed to 10 or 29 subjects under the same Simon’s Optimal 
2-stage design as for the other cohorts for better assessment of activity in that disease 
subpopulation (Optional Cohort F expansion). It is expected that no more than 2 subpopulations 
will be expanded in this manner.
11.2.
Analysis Sets to Be Analyzed
11.2.1.
All Subject Analysis Set
The All Subject Analysis Set will include information from all screened subjects, including those 
who did not meet the study entry criteria or did not receive a study treatment. This data set will 
only be used for disposition in which all screened subjects are accounted for. 
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11.2.2.
Efficacy Analysis Set
The Efficacy Analysis Set will include all subjects who receive any amount of study treatment 
for efficacy analyses. Efficacy analyses will be based on the actual treatment received. The ORR 
and DCR analysis will be based on subjects who are in the Efficacy Analysis Set and who had 
disease assessment at baseline and at least 1 follow up disease assessment or subjects who died 
or stopped treatment before the first scheduled disease assessment due to clinical progression or 
toxicity.
11.2.3.
Safety Analysis Set
The Safety Analysis Set will include data from all subjects who receive any amount of study 
drug. Safety analysis will be based on the actual treatment received. All data will be included, 
and no subjects excluded because of protocol violations. 
11.2.4.
PK Analysis Set
The PK Analysis Set will consist of all available plasma concentrations and PK parameters for 
ASTX029 from subjects who have received study drug and for whom PK samples were collected 
and successfully analyzed.
11.2.5.
Pharmacodynamic and Biomarker Analysis Set
Subjects will be included in the pharmacodynamic and biomarker analyses if they have received 
study drug and their samples were successfully collected and analyzed. 
11.3.
Schedule of Analyses
This is an open-label study. Ongoing analyses to help manage the study and support the DSRC 
reviews for safety and antitumor activity will be undertaken. A final analysis will be conducted 
after all subjects have completed the study.
11.4.
Disposition
The number and percentage (n, %) of subjects enrolled, treated, lost to follow-up, and withdrawn 
from treatment or discontinued from the study (with reason) will be summarized. The sample 
sizes for the Efficacy Analysis Set, Safety Analysis Set, PK Analysis Set, and Pharmacodynamic 
and Biomarker Analysis Set will be clearly identified. All subjects in the All Subject Analysis 
Set will be included in the disposition analysis. 
Summaries will be provided separately for each regimen in Phase 1 Part A, for the RDE 
cohort(s) in Phase 1 Part B, and for the RP2D in Phase 2.
11.5.
Analysis of Demographic and Baseline Data
Subject demographic and baseline characteristics will be summarized by mean, standard 
deviation, median, minimum, and maximum for continuous variables; and by counts and 
percentages for categorical variables. All subjects who received any amount of study drug (ie, 
the Safety Analysis Set) will be included in the analysis of demographic and baseline 
characteristics.
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Summaries will be provided separately for each regimen in Phase 1 Part A, for the RDE 
cohort(s) in Phase 1 Part B, and for each cohort in Phase 2.
11.6.
Efficacy Analyses
Analyses for all efficacy endpoints will be provided separately for each treatment regimen in 
Phase 1 Part A and for the RDE cohort(s) in Phase 1 Part B, and for each cohort in Phase 2.
11.6.1.
Objective Response and Disease Control Rate
The ORR will be calculated as the number of evaluable subjects whose best response is CR or 
PR, divided by the total number of subjects evaluable for ORR analysis (Section 11.2.2). The 
DCR will be calculated as the number of subjects whose best response is CR, PR, or stable 
disease (SD), divided by the total number of subjects evaluable for DCR analysis 
(Section 11.2.2). The 90% Clopper-Pearson confidence intervals (Cis) for the ORR and DCR 
will be provided.
11.6.2.
Progression-free Survival
The PFS is defined as the number of days from the start of the study treatment to disease 
progression or death, whichever occurs first. The PFS will be analyzed using a Kaplan-Meier 
method, with PFS time being censored on the date of the last disease assessment. The 90% CI for 
median PFS will be provided using the Kaplan-Meier procedure. All subjects in the Efficacy 
Analysis Set will be included in the PFS analysis.
11.6.3.
Overall Survival
The OS is defined as the number of days from the day the subject was randomized to the date of 
death (regardless of cause). Subjects without a documented death date will be censored on the 
last date they were known to be alive. The OS will be presented using a Kaplan-Meier estimate. 
The 90% CI for median OS will be provided using the Kaplan-Meier procedure. All subjects in 
the Efficacy Analysis Set will be included in the OS analysis. 
11.6.4.
Duration of Response
Duration of response will be calculated for all responders from the date of the earliest assessment 
of CR or PR to the date of relapse or death, whichever occurs earlier, or the last disease 
assessment date for subjects without a relapse or death. Duration of SD will be calculated for 
subjects whose best response is CR, PR, or SD from the day study drug was first taken to the 
date of disease progression or death, whichever occurs earlier, or the last disease assessment for 
subjects without disease progression or death.
Duration of response and duration of SD will be summarized with descriptive statistics including 
arithmetic mean, standard deviation, median, and range will be summarized for subjects who 
have overall responses. 
11.7.
Safety Analyses
Safety will be assessed by subject-reported and investigator-observed Aes along with 
concomitant medications, Pes, clinical laboratory tests (hematology, coagulation, serum 
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chemistry, and urinalysis), vital signs, ECOG performance status, ECGs, and ECHO/MUGA 
scans. 
All Aes will be mapped to the appropriate System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA). Severity of Aes will 
be graded using CTCAE v4.03 (Appendix 2). All Aes collected during the study will be 
presented in data listings. TEAEs are defined as events that first occur or worsen after the subject 
receives study drug on C1D1 until 30 days after the last dose of study treatment, or the start of an 
alternative anticancer treatment, whichever occurs first, to be defined in more detail in the 
statistical analysis plan. Summaries will be provided by SOC and PT for all Aes, Aes considered 
related to study treatment, SAEs, and related SAEs as follows based on the treatment period 
when the events occur. Similar summaries will also be generated by maximum severity. In 
addition, exposure to ASTX029, reasons for discontinuation, deaths, and causes of deaths will be 
tabulated. 
The number and proportion of subjects who have DLTs, as defined in Section 7.4, will be 
summarized by cohort and regimen in Phase 1 Part A.
Laboratory values reported by different local labs will be listed. Shift tables will be provided for 
each graded laboratory test.
Concomitant medications are the medications taken with a start date on or after the start of the 
administration of study treatment (C1D1) or those with a start date before the start of the 
administration of study treatment (C1D1) and a stop date on or after the start of study drug 
administration (C1D1) as to be defined in more detail in the statistical analysis plan. 
Concomitant medication will be coded by the World Health Organization (WHO) Global List 
and summarized by therapeutic subgroup (Anatomical Therapeutic Chemical [ATC] level 2) and 
PT, sorted alphabetically, using counts and percentages.
Vital sign measurements will be summarized by visit using the proportion of subjects with each 
vital sign being too high or too low according to conventionally accepted vital sign normal 
ranges. Physical examination, ECOG performance status, and ECG findings will be listed in data 
listings or analyzed with summary tables.
11.8.
Pharmacokinetic Analyses
The PK Analysis Set (Section 11.2.4) will be used for PK analyses.
The PK parameters will be derived for each subject using a noncompartmental approach. 
Descriptive statistics including mean, standard deviation, median, and range for PK parameters 
for ASTX029 will be summarized separately for each regimen and by dose within each regimen. 
Detailed and additional PK analyses are described in a separate PK analysis plan.
11.9.
Pharmacodynamic/Biomarker Analyses
The Pharmacodynamic and Biomarker Analyses Set (Section 11.2.5) will be used for 
pharmacodynamic and biomarker analyses.
Values at baseline and changes from baseline (if appropriate) of the pharmacodynamic 
parameters and biomarkers assessed in the study will be summarized descriptively using mean, 
standard deviation, median, minimum, and maximum for continuous variables and counts and 
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percentages for categorical variables. Summaries will be provided separately for each regimen in 
Phase 1 Part A, for the RDE cohort(s) in Phase 1 Part B, and for each cohort in Phase 2. 
11.10.
Interim Analysis
No interim analysis is planned for this open-label study. The data will be reviewed in an ongoing 
manner in conjunction with dose-escalation decisions and general safety monitoring.
11.11.
Procedures for Handling Missing, Unused, and Spurious Data
No imputation of values for missing data will be performed unless specified otherwise in the 
statistical analysis plan. Data from subjects lost to follow-up will be included in statistical 
analyses to the day of last contact. 
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12.
STUDY DURATION AND TERMINATION
The expected study duration is approximately 5 years (61 months), including approximately 
55 months for recruitment and approximately 6 months for safety follow-up. 
The Sponsor may stop the study at any time. In case of this event, the Sponsor will make 
reasonable efforts to ensure subjects are transitioned off study in an orderly manner. Reasons for 
early termination include, but are not limited to, lack of preliminary clinical activity or safety 
concerns. 
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13.
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS
13.1.
Compliance Statement
The study will be conducted in accordance with the ICH GCP guidelines, principles enunciated 
in the Declaration of Helsinki, and all human clinical research regulations in countries where the 
study is conducted.
13.2.
Informed Consent
The ICFs used for the study must comply with the Declaration of Helsinki, federal regulations 
US 21 Code of Federal Regulations (CFR) Part 50, and ICH GCP guidelines and any other local 
regulations. The investigator, or a person delegated by the investigator, must explain the medical 
aspects of the study, including the nature of the study and the treatment, orally and in writing, in 
such a manner that the subject is aware of potential benefits and risks. Subjects must be informed 
that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. Subjects, or a legal guardian if the subject is unable to, must give informed consent in 
writing.
The informed consent process must be conducted, documented in the source document 
(including the date), and the form must be signed, before the subject undergoes any study-
specific procedures.
13.3.
Institutional Review Board or Independent Ethics Committee 
(IRB/IEC)
The investigator must submit the protocol, protocol amendments, and the ICF for the proposed 
study, along with any other documents required by the center’s IRB/IEC to the center’s duly 
constituted IRB/IEC for review and approval. The investigator must also ensure that the IRB/IEC 
reviews the progress of the study on a regular basis and, if necessary, renews its approval of the 
study on an annual basis. A copy of each IRB/IEC approval letter must be forwarded to the 
sponsor before the study is implemented. Documentation of subsequent reviews of the study 
must also be forwarded to the sponsor.
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14.
ADMINISTRATIVE PROCEDURES
14.1.
Sponsor Responsibilities
The Sponsor reserves the right to terminate the study and remove all study materials from a study 
center at any time. The Sponsor and the investigators will assure that adequate consideration is 
given to the protection of the subjects’ interests. Specific circumstances that may precipitate such 
termination are:

Request by Health Authority to terminate the study.

Unsatisfactory subject enrollment with regard to quality or quantity.

Significant or numerous deviations from study protocol requirements, such as failures 
to perform required evaluations on subjects, maintain adequate study records or 
inaccurate, incomplete or late data recording on a recurrent basis.

The incidence or severity of AEs in this or other studies indicating a potential health 
hazard caused by the study treatment.
14.1.1.
Study Supplies
The sponsor will supply sufficient quantities of the following materials to each clinical center:

ASTX029 as described in Section 7.

VFR as described in Section 7.

IB for ASTX029.

Case report forms or data collection tools.
14.1.2.
Investigator Training
All study centers will have a center-specific study initiation meeting to ensure the center staff 
understand the protocol, study requirements, and data capture processes. This training will take 
place before the first subject is enrolled. Each study center will be provided with information 
regarding GCP and regulations specific to the conduct of clinical studies. Each center is 
responsible for ensuring that new team members are adequately trained and the training is 
documented.
14.1.3.
Ongoing Communication of Safety Information During the Study
The sponsor will provide the investigator with documentation of SAEs, from this study and other 
studies, that are related to ASTX029 and unexpected (see Section 10.2.4), as appropriate. The 
investigator must forward this documentation to the IRB/IEC, as described in Section 10.2.4. 
The sponsor will also notify the investigator about any other significant safety findings that could 
alter the safety profile of the IMP from what is described in the protocol and significantly affect 
the safety of subjects, affect the conduct of the study, or alter the IRB/IEC’s opinion about 
continuation of the study. This does not include safety issues that could be mitigated by simple 
changes in the protocol decided by the DSRC (Section 4.4) such as limiting some of the 
eligibility criteria or reducing the IMP dose or dosing schedule.
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14.1.4.
Study Monitoring
Representatives of the Sponsor will monitor the study. Routine monitoring visits will be 
conducted to:

Assure compliance with the study protocol and appropriate regulations.

Verify that (1) the informed consent process was conducted before initiation of any 
study-specific procedures (ie, performed solely for the purpose of determining 
eligibility for the study) and before provision of study treatment, and (2) this process 
is adequately documented.

Verify that the protocol, protocol amendments, and safety information are submitted 
to the IRB/IECs and approved by the IRB/IECs in a timely manner.

Review the eCRFs and source documents to ensure that reported study data are 
accurate, complete, and verifiable from source documents.

Verify that study treatments are stored properly and under the proper conditions, that 
they are in sufficient supply, and that receipt, use, and return of ASTX029 at the 
study centers are controlled and documented adequately.

Verify that the investigator and study center personnel remain adequately qualified 
throughout the study.

Verify that the research facilities, including laboratories and equipment, are 
maintained adequately to safely and properly conduct the study.
14.1.5.
Study Auditing and Inspecting
The sponsor may audit the study conduct, compliance with the protocol and accuracy of the data 
in 1 or more centers. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, and inspections by 
the Sponsor, IRB/IEC, government regulatory bodies and Taiho Quality Assurance personnel or 
its designees by providing direct access to source data/documents after appropriate notification 
from sponsor.
14.2.
Investigator Responsibilities
14.2.1.
Subject Screening Log
The investigator must keep a record that lists all subjects who signed an informed consent and 
the reason for non-inclusion if they were not ultimately enrolled, randomized, or treated.
14.2.2.
ASTX029 and VFR Accountability
Initial supplies of ASTX029 and VFR will be shipped to each study center’s pharmacy when all 
the initiation documents, including IRB/IEC approvals, IRB/IEC approved ICF, and business 
agreements, have been received and reviewed by the Sponsor and upon activation of the study 
center by the Sponsor. Resupply of ASTX029 and VFR will be managed by the IRT system. The 
study center will be responsible for ensuring the inventory in the IRT system is accurate to 
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ensure resupply occurs as needed. Until ASTX029 PiB was phased out, initial supplies of VFR 
were shipped to each study center’s pharmacy when conditions as described above were met.
Keep ASTX029 and VFR in a locked, limited-access room. The study treatment must not be 
used outside the context of the protocol. Under no circumstances should the investigator or other 
study center personnel supply ASTX029 or VFR to other investigators, subjects, or clinics or 
allow supplies to be used other than as directed by this protocol without prior authorization from 
the Sponsor. 
The monitor will regularly review and verify all ASTX029 and VFR supplies and associated 
documentation.
Maintain an accurate accounting of the study treatments. These records must show dates, lot 
numbers, quantities received, dispensed, and returned and must be available for monitoring by 
the sponsor. The investigator will ensure that any used and unused ASTX029, VFR, and other 
study material is destroyed or returned to the sponsor on completion of the study. If the 
ASTX029 or VFR is destroyed at the study center, there should be documentation of destruction 
at the study center. The sponsor and/or their representatives will verify final drug accountability. 
ASTX029 and VFR accountability records must be maintained and readily available for 
inspection by representatives of the Sponsor and are open to inspections by regulatory authorities 
at any time.
14.2.3.
Reporting and Recording of Study Data
Data will be captured and compiled using procedures developed by the sponsor or their 
representatives. Clearly record all requested study data on the eCRF and other study forms as 
required. Whenever possible, record the reason for missing data in the source document. Only 
individuals who are identified on the study personnel responsibility/signature log may enter or 
correct data in the eCRF. Incomplete or inconsistent data on the eCRFs will result in data queries 
that require resolution by the investigator or designee.
The investigator must assure subject anonymity and protection of identities from unauthorized 
parties. On eCRFs or other documents or subject records provided to the Sponsor, identify 
subjects by code (subject number, initials, date of birth) and not by names. The principal 
investigator should maintain documents not for submission to the Sponsor (eg, subject’s signed 
informed consent), in strict confidence.
14.2.4.
Source Documentation
The investigator must maintain adequate and accurate source documents upon which eCRFs for 
each subject are based. They are to be separate and distinct from eCRFs, except for cases in 
which the sponsor has predetermined that direct data entry into specified pages of the subject’s 
eCRF is appropriate. These records should include detailed notes on:

The oral and written communication with the subject regarding the study treatment 
(including the risks and benefits of the study). Record the date of informed consent in 
the source documentation.

The subject’s medical history before participation in the study.
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
The subject’s basic identifying information, such as demographics, that links the 
subject’s source documents with the eCRFs.

The results of all diagnostic tests performed, diagnoses made, therapy provided, and 
any other data on the condition of the subject.

The subject’s exposure to study treatment.

All AEs.

The subject’s exposure to any concomitant therapy (including start and stop dates, 
route of administration, and dosage).

All relevant observations and data on the condition of the subject throughout the 
study.
14.2.5.
Tissue and Blood Sample Collection/Storage
Tissue and blood components samples which are collected as part of routine medical care or as 
part of protocol procedures may be stored and analyzed for PK or pharmacodynamic and other 
biomarker analyses. 
After the study, samples may be used for additional investigation to help identify factors that 
may influence response to therapy. Such samples will be used in compliance with guidelines 
defined by FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using 
Leftover Human Specimens that are Not Individually Identifiable (issued 25 April 2006) and 
European Agency for the Evaluation of Medicinal Products (EMEA)’s Reflection Paper on 
Pharmacogenomic Samples, Testing and Data Handling (EMEA 2007). 
If a subject withdraws consent, they may request destruction of any samples taken and not tested 
yet, and the investigator must document this in the site study records and inform the sponsor 
within 24 hours. 
14.2.6.
Records Retention
The investigator must ensure that clinical study records are retained according to national 
regulations, as documented in the clinical trial agreement entered into with the sponsor in 
connection with this study. The investigator will maintain all records and documents pertaining 
to the study including, but not limited to, those outlined above (see Section 14.2.4) for a period 
of: at least 2 years after FDA approval of the drug or at least 2 years after withdrawal of the IND 
under which this study was conducted, whichever is longer. In countries outside the US, records 
must be kept for the period of time required by the US FDA as a minimum, and record retention 
should also comply with the local country regulatory requirements, if longer retention times are 
required than in the US. Mandatory documentation includes copies of study protocols and 
amendments, financial disclosures, each FDA Form 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE Report forms transmitted to the Sponsor, subject files 
(source documentation) that substantiate entries in eCRFs, all relevant correspondence, and other 
documents pertaining to the conduct of the study. These records must remain in each subject's 
study file and be available for verification by study monitors at any time.
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The investigator must inform the sponsor immediately if any documents are to be destroyed, 
transferred to a different facility, or transferred to a different owner. The sponsor should be given 
the option of collecting the documents before destruction.
14.3.
Clinical Trial Insurance
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating 
study centers upon request.
14.4.
Study Administrative Letters and Protocol Amendments
The Sponsor may issue Study Administrative Letters (1) to clarify certain statements or correct 
obvious errors/typos/inconsistencies in the study protocol, (2) to change the logistical or 
administrative aspects of the study, such as study personnel or contact information, or (3) to 
instruct investigators of DSRC safety decisions for immediate implementation for safety reasons
(Section 4.4). 
For all other changes, the Sponsor will initiate any change to the protocol in a protocol 
amendment document. The study center will submit the amendment to the IRB/IEC together 
with, if applicable, a revised model ICF. If the change in any way increases the risk to the 
subject, information on the increased risk must be provided to subjects already actively 
participating in the study, and they must read, understand, and sign any revised ICF confirming 
willingness to remain in the study.
The investigator must obtain IRB/IEC approval before any protocol amendment can be 
implemented, except for administrative changes or changes necessary to eliminate an immediate 
risk to study subjects, as outlined above.
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15.
POLICY FOR PUBLICATION AND PRESENTATION OF DATA
The sponsor encourages the scientific publication of data from clinical research studies. 
However, investigators may not present or publish partial or complete study results individually 
without review by the sponsor. The principal investigators and the sponsor may propose 
appropriate scientific manuscripts or abstracts from the study data. The sponsor must review and 
comment on all proposed publications before submission for publication. The detailed 
procedures for the review of publications are set out in the clinical trial agreement entered into 
with the sponsor in connection with this study. These procedures are in place to ensure 
coordination of study data publication and adequate review of data for publication against the 
validated study database for accuracy. Names of all investigators and sponsor representatives 
responsible for designing the study and analyzing the results will be included in the 
publication(s).
Qualification of authorship will follow the requirements of the International Committee of 
Medical Journal Editors (www.icmje.org). In most cases, the principal investigators at the 
centers with the highest participation in the study shall be listed as lead authors on manuscripts 
and reports of study results. In addition, other than clinical pharmacology studies in healthy 
volunteers or Phase 1 studies, all clinical studies must be registered with ClinicalTrials.gov.
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16.
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17.
APPENDICES
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APPENDIX 1.
ECOG PERFORMANCE STATUS
Score
ECOG Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (eg, light house work, office work)
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source: ECOG Performance Status  https://ecog-acrin.org/resources/ecog-performance-status/
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APPENDIX 2.
NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS
Adverse events and/or adverse drug reactions will be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03.
View the National Cancer Institute (NCI) CTCAE electronically at the following website:
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf .
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APPENDIX 3.
RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS, VERSION 1.1
The information is this appendix is based on RECIST v1.1 (Eisenhauer et al 2009). 
Measurability of Tumor at Baseline
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable, as 
described below:
Measurable

Tumor lesions:  Must be accurately measured in at least 1 dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm).

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as nonmeasurable).

20 mm by chest X-ray.

Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be 15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm). At baseline (ie, 
screening for this study) and in follow-up (ie, all measurements past screening for this 
study), only the short axis will be measured and followed. See also notes below on 
‘Baseline documentation of target and nontarget lesions’ for information on lymph 
node measurement.
Nonmeasurable
All other lesions, including small lesions (longest diameter 10 mm or pathological lymph nodes 
with 10 to 15 mm short axis) as well as truly nonmeasurable lesions. Lesions considered truly 
nonmeasurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment.
Bone Lesions

Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
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or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above.

Blastic bone lesions are nonmeasurable.
Cystic Lesions

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they 
are, by definition, simple cysts.

'Cystic lesions' thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions.
Lesions With Prior Local Treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion. 
Specifications by Methods of Measurements
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
NEVER more than 21 days before the beginning of the treatment.
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
Magnetic resonance imaging (MRI) is also acceptable in certain situations (eg, for body scans). 
Tumor Response Evaluation
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. In this study, only 
subjects with measurable disease at baseline should be included in the study.
Baseline Documentation of 'Target' and 'Nontarget' Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total representative of all involved organs should be identified as target lesions and will 
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be recorded and measured at baseline. In instances where subjects have only 1 or 2 organ sites 
involved, a maximum of 2 and 4 lesions respectively will be recorded.
The criteria for selection of target lesions are as follows:
Largest in size (ie, lesions with the longest diameter). If the largest lesion does not lend itself to 
reproducible measurement, the next largest lesion that can be measured reproducibly should be 
selected.
a.
Representative of all involved organs. 
b. Can be repeatedly measured using a reproducible method. 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node that is reported as being 20 × 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis 10 mm but 15 mm) 
should be considered nontarget lesions. Nodes that have a short axis 10 mm are considered 
nonpathological and should not be recorded or followed.
A sum of the diameters (longest for nonnodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal 
progression.’ In addition, it is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
Response Criteria
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions.
Evaluation of Target Lesions
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to <10 mm.
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.
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Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also 
considered progression).
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Special Notes on the Assessment of Target Lesions
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of 10 mm. For PR, SD, and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’: While on study, all lesions (nodal and 
nonnodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
‘too small to measure.’ When this occurs, it is important that a value be recorded on the eCRF. If 
it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should 
be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: it is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5-mm thickness of CT scan 
slices (but should not be changed with varying CT slice thickness). The measurement of these 
lesions is potentially nonreproducible; therefore providing this default value will prevent false 
responses or progressions based upon measurement error. To reiterate, however, if the 
radiologist is able to provide an actual measure, that value should be recorded, even if it is below 
5 mm.
Lesions that split or coalesce on treatment: When nonnodal lesions ‘fragment,’ the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’.
Evaluation of Nontarget Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of nontarget lesions. While some nontarget lesions may actually be measurable, they need 
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not be measured, and instead should be assessed only qualitatively at the time points specified in 
the protocol. 
CR: Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph 
nodes must be nonpathological in size (10 mm short axis).
Non-CR/Non-PD: Persistence of 1 or more nontarget lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
PD: Unequivocal progression (see comments below) of existing nontarget lesions (Note: the 
appearance of 1 or more new lesions is also considered progression).
Special Notes on Assessment of Progression of Nontarget Disease
The concept of progression of nontarget disease requires additional explanation as follows, when 
the subject also has measurable disease. In this setting, to achieve ‘unequivocal progression’ on 
the basis of the nontarget disease, there must be an overall level of substantial worsening in 
nontarget disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the 
size of 1 or more nontarget lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
nontarget disease in the face of SD or PR of target disease will therefore be extremely rare. 
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of preexisting lesions). This is particularly important 
when the subject’s baseline lesions show PR or CR. For example, necrosis of a liver lesion may 
be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered that reveals metastases. The subject’s brain metastases are considered to be evidence of 
PD even if they did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment. No confirmatory measurement for CR, PR, or SD is required in the study.
The subject’s best overall response assignment will depend on the findings of both target and 
nontarget disease and will also take into consideration the appearance of new lesions.
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Time Point Response
Please follow the per-protocol time point response assessments. Table 14 below provides a 
summary of the overall response status calculation at each time point for subjects who have 
measurable disease at baseline. 
Table 14:
Overall Response
Time Point Response: Subjects with Target (±Nontarget) Disease
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
Pd
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes 
PD
CR=complete response, NE=inevaluable, PD=progressive disease, PR=partial response; SD=stable disease.
Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at a particular time point, the subject is not evaluable at 
that time point. If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered not evaluable at that time point, unless a convincing argument can be 
made that the contribution of the individual missing lesion(s) would not change the assigned time 
point response. This would be most likely to happen in the case of PD. For example, if a subject 
had a baseline sum of 50 mm with 3 measured lesions and at follow-up only 2 lesions were 
assessed, but those gave a sum of 80 mm, the subject will have achieved PD status, regardless of 
the contribution of the missing lesion. 
Best Overall Response: All Time Points
The best overall response is determined once all the data for the subject is known.
Best response determination in studies where confirmation of CR or PR is not required: Best 
response in these studies is defined as the best response across all time points (eg, if a subject has 
SD at first assessment, PR at second assessment, and PD on last assessment, he or she will have 
a best overall response of PR). When SD is believed to be best response, it must also meet the 
protocol-specified minimum time from baseline (6 weeks). If the minimum time is not met when 
SD is otherwise the best time point response, the subject’s best response depends on the 
subsequent assessments. For example, if a subject has SD at first assessment, but PD at the 
second assessment, and does not the meet minimum duration for SD, he or she will have a best 
response of PD. The same subject lost to follow-up after the first SD assessment would be 
considered inevaluable.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement should 
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be recorded even though the nodes are normal, in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that subjects with CR may not 
have a total sum of ‘zero’ on the eCRF.
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration.’ Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such subjects is to be determined by evaluation of target and nontarget disease.
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.
Frequency of Tumor Re-evaluation
In this study, tumor measurement will be conducted at the end of every 2 cycles (±7 days) for the 
first 4 cycles and then every 4 cycles (±1 cycle) thereafter until clinical and/or radiographic 
disease progression, or death, or the subject withdraws consent. Scan dates should not be 
adjusted or rescheduled due to dose interruption of any type. 
Baseline tumor assessments must be performed within 3 weeks (21 days) prior to the first dose of 
treatment. 
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, technique
(including slice thickness and field of view), and radiographic interpreter.
The radiographic evaluation must include CT or MRI scanning of the known sites of 
involvement, as well as the chest, abdomen, and pelvis if they are not the primary target. Any 
additional suspected sites of disease should also be imaged. All evaluations should meet the 
standard of care for imaging of lesions in the respective organ(s) and should conform to the 
image acquisition guidelines according to institutional standards.
All target and nontarget sites are evaluated at each time point of tumor assessment.
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APPENDIX 4.
MANAGEMENT OF SKIN TOXICITIES
Cutaneous adverse events have been observed in subjects receiving MEK inhibitors (ie, 
trametinib [Mekinist USPI] and cobimetinib [Cotellic USPI]) and ERK inhibitors (ulixertinib 
and GDC-0994) (de la Cruz-Merino et al 2017; Sullivan et al 2018; Li et al presentation 2017, 
Varga et al 2020; Infante et al abstract 2015; Infante et al presentation 2015; Macdonald et al 
2015; Reyes-Habito et al 2014; Anforth et al 2013; Mandalà et al 2013; Manousaridis et al 
2013). 
Suggested guidelines regarding management and criteria for adjusting, withholding, and 
discontinuing study treatment for skin toxicities considered to be related to study treatment are 
provided in Table 15. The institutional standards for the management of skin-related AEs can 
differ from these guidelines. In this case, best clinical judgment should be applied.
Table 15:
Suggested Management and Dose Modification Guidelines for Skin Toxicities
CTCAE 
Grade
Management
Action and Dose Modification
Grade 1

Initiate symptomatic measures.

Use moderate strength topical steroid.a

Consider topical antibiotics or combined topical 
steroids/antibiotics if acneiform papulopustular rash.

Consider oral antibiotics.

Consider oral antihistamines if maculopapular rash.

Reassess after 1 week.

Continue study treatment and 
monitor for change in severity.

If no recovery to ≤Grade 1 
within 2 weeks despite best 
supportive care, reduce study 
treatment by 1 dose level.b
Grade 2

Initiate symptomatic measures.

Use moderate strength topical steroid.a

Obtain bacterial/viral/fungal cultures if infection is 
suspected.

Initiate topical antibiotics and, if rash is persistently ≥Grade 
2 after 1 week, initiate oral antibiotics for 6 weeks 
(doxycycline 100 mg BID or minocycline 100 mg BID) if 
acneiform papulopustular rash. Initiation of oral antibiotics 
at first sign of Grade 2 acneiform papulopustular rash is 
also appropriate.

Initiate oral antihistamines or oral steroidc if maculopapular 
rash.

Consider dermatology referral for evaluation and biopsy.

Reassess after 1 week.

Reduce study treatment by 
1 dose level.

After reduction, if recovery to 
≤Grade 1, increase dose to 
previous dose level.

After reduction, if no recovery to 
≤Grade 1 within 1 week, 
interrupt study treatment until 
recovery to ≤Grade 1 and restart 
with study treatment reduced by 
1 dose level.d
Grade ≥3

Initiate symptomatic measures.

Use moderate strength topical steroida plus oral steroids.

Obtain bacterial/viral/fungal cultures if infection is 
suspected.

Initiate oral antibiotics (doxycycline 100 mg BID or 
minocycline 100 mg BID or oxytetracycline 500 mg BID) if 
acneiform (papulopustular) rash. 

Initiate oral antihistamines if maculopapular rash.

Consider dermatology referral for evaluation and biopsy.

Reassess after 1 week.

Interrupt study treatment until 
recovery to ≤Grade 1.d

Restart with study treatment 
reduced by 1 dose level.b

If no recovery to ≤Grade 1 
within 3 weeks, permanently 
discontinue study treatment.
BID=twice a day; CTCAE=Common Terminology Criteria for Adverse Events.
a Hydrocortisone 2.5% cream or fluticasone 0.5% cream.
b Escalation to previous dose level may be considered if no skin toxicity is evident for 4 weeks after restarting study treatment.
c Prednisolone 0.5 mg/kg/day or equivalent (up to 60 mg/kg/day) for 5 to 7 days.
d Approval of the Sponsor’s medical monitor is required to restart study treatment after interruption ≥21 days.
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Preventative care measures for skin toxicities should include:

Avoid sun exposure.

Apply broad spectrum sunscreen twice daily (SPF >15). 

Use thick, alcohol-free emollient cream on dry areas at least twice daily.
Symptomatic care should include:

Pruritic lesions: cool compresses and oral antihistamine.

Paronychia: antiseptic bath, oral antibiotic, and local corticosteroids.

Fissuring lesions: silver nitrate or zinc oxide cream.

Desquamation: emollients and mild soap.
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APPENDIX 5.
MANAGEMENT OF VISUAL CHANGES
Ocular adverse events have been observed in subjects receiving MEK inhibitors (ie, trametinib 
[Mekinist USPI] and cobimetinib [Cotellic USPI]) and ERK inhibitors (ulixertinib and GDC-
0994 [de la Cruz-Merino et al 2017; Sullivan et al 2018; Li et al presentation 2017; Maubon et al 
2016; Stjepanovic et al 2016; Varga et al 2020; Duncan et al 2015; Infante et al abstract 2015; 
Infante et al presentation 2015; Welsh and Corrie 2015; Ho et al 2013]). Ocular toxicities include 
blurring and altered light perception, periorbital edema, increased lacrimation, uveitis, and visual 
disturbances. Retinal adverse events have also been described in subjects receiving MEK 
inhibitors (de la Cruz-Merino et al 2017; Stjepanovic et al 2016; Welsh and Corrie 2015). 
The causal relationship between a change in vision and the study treatment should be carefully 
explored, and an ophthalmologist should be consulted. Special attention should be given to 
retinal adverse events (eg, CSR, RVO). For events of visual changes regardless of severity, a 
blood sample for PK analysis must be drawn as close as possible to the time of the event. 
Suggested guidelines regarding management and criteria for adjusting, withholding, and 
discontinuing study treatment for visual changes considered to be related to study treatment are 
provided in Table 16. The institutional standards for the management of ocular AEs can differ 
from these guidelines. In this case, best clinical judgment should be applied.
Table 16:
Suggested Management and Dose Modification for Visual Changes
CTCAE 
Grade
Management
Action and Dose Modification
Grade 1
Consult 
ophthalmologist 
within 7 days of 
onset

Continue study treatment.

If dilated fundus examination cannot be performed within 7 days of onset, 
interrupt study drug.

If RVO or CSR excluded, continue study treatment at the same dose level.

If CSR suspected or diagnosed, continue study treatment at the same dose level. 
If RVO diagnosed, permanently discontinue study treatment and report as an 
SAE.
Grade 2
Interrupt study 
treatment and 
consult 
ophthalmologist 
immediately

If RVO or CSR excluded, resume study treatment at the same dose level. 

If CSR diagnosed, withhold study treatment. If improved to ≤Grade 1, resume 
at a lower dose levela with close monitoring following treatment re-initiation. 

If RVO diagnosed, permanently discontinue study treatment and report as an 
SAE.
Grade 3
Interrupt study 
treatment and 
consult 
ophthalmologist 
immediately

If RVO or CSR excluded, withhold study treatment. If improved to ≤Grade 1, 
resume at a lower dose level. 

If CSR diagnosed, withhold study treatment. If improved to ≤Grade 1, resume 
at a lower dose levela with close monitoring following treatment re-initiation.

If RVO diagnosed, permanently discontinue study treatment and report as an 
SAE.
Grade 4 
Interrupt study 
treatment and 
consult 
ophthalmologist 
immediately

Permanently discontinue study treatment and report as an SAE.
CSR=central serous retinopathy; CTCAE=Common Terminology Criteria for Adverse Events; RVO=retinal vein occlusion; 
SAE=serious adverse event.
a Dose level depends on the nature of the ocular toxicity. Approval of the Sponsor’s medical monitor is required to restart study 
treatment after interruption ≥21 days.
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APPENDIX 6.
MANAGEMENT OF DIARRHEA
Episodes of diarrhea have occurred in subjects receiving MEK inhibitors (ie, trametinib 
[Mekinist USPI] and cobimetinib [Cotellic USPI]) and ERK inhibitors (ulixertinib and GDC-
0994) (Adjei et al, 2017; Sullivan et al 2018; Li et al presentation 2017; Varga et al 2020; Infante 
et al abstract 2015; Infante et al presentation 2015; Welsh and Corrie 2015). 
Suggested guidelines regarding management and criteria for adjusting, withholding, and 
discontinuing study treatment for diarrhea considered to be related to study treatment are 
provided in Table 17. The institutional standards for the management of GI AEs can differ from 
these guidelines. In this case, best clinical judgment should be applied.
Table 17:
Suggested Management and Dose Modification for Diarrhea
CTCAE Grade
Management
Action and Dose Modification
Uncomplicateda 
Grade 1 or 2

Diet: stop lactose-containing products; BRAT diet 
recommended.

Hydration: 8 to 10 large glasses per day.

Loperamideb: Initially 4 mg followed by 2 mg every 
four hours; maximum 16 mg/day. Continue until 
diarrhea-free for 12 hours.

Diarrhea >24 hours: loperamide every 2 hours, 
maximum 16 mg/day. Consider adding oral 
antibiotics.

Diarrhea >48 hours: loperamide every 2 hours; 
maximum 16 mg/day. Consider second-line therapies 
(budesonide, tincture of opium, or octreotide) and 
oral antibiotics.

Rule out other causes (eg, infection).

Continue study treatment.

If diarrhea is Grade 2 for 
>48 hours, interrupt study 
treatment until diarrhea resolves 
to ≤Grade 1.c

Resume study treatment at the 
same dose level.
Uncomplicateda 
Grade 3 

Diet: stop lactose-containing products; BRAT diet 
recommended.

Hydration: 8 to 10 large glasses per day.

Loperamideb: Initially 4 mg followed by 2 mg every 
four hours; maximum 16 mg/day. Continue until 
diarrhea-free for 12 hours.

Second-line therapies and antibiotics if clinically 
indicated.

Hydration: IV fluids if clinically indicated.

Rule out other causes (eg, infection).

Inform the Sponsor’s medical 
monitor

Interrupt study treatment until 
diarrhea resolves to ≤G1.c

Resume with study treatment at a 
lower dose level.e
Grade 4
Any complicatedd 
diarrhea

Urgent intervention indicated.

Intervention may require hospitalization for subjects 
at risk of life-threatening complications. 

Inform the Sponsor’s medical 
monitor.

Permanently discontinue study 
treatment and report as an SAE.
BRAT=bananas, rice, applesauce, toast; CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; 
SAE=serious adverse event.
a Uncomplicated diarrhea defined by the absence of symptoms.
b Loperamide should be made available before study treatment so that administration can start at the first signs of diarrhea.
c Approval of the Sponsor’s medical monitor is required to restart study treatment after ≥21 days interruption
d Complicated diarrhea defined by the presence of symptoms such as pyrexia, sepsis, neutropenia ≥Grade 3, frank bleeding, 
and/or dehydration requiring IV fluid substitution.
e Escalation of study treatment to previous dose level may be allowed after consultation with the Sponsor’s medical monitor and 
in the absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction.
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APPENDIX 7.
LIVER STATUS MONITORING AND MANAGEMENT OF 
POTENTIAL LIVER INJURY
Liver enzyme elevation has been observed in patients receiving ERK inhibitors (Sullivan et al 
2018; Li et al presentation 2017; Varga et al 2020; Infante et al abstract 2015; Infante et al 
presentation 2015). Clinical symptoms and laboratory test values that are potential signals of 
liver injury must be regularly reviewed by investigators and by the Sponsor’s medical monitor 
for the study. 
Discontinuation of study treatment should occur if a subject shows potential signals of liver 
injury, indicated by the occurrence of any of the following liver function test values. (Note: liver 
toxicity or injury may be confirmed with a liver biopsy, if clinically indicated.)

ALT or AST ≥8×ULN. 

ALT or AST >5×ULN but <8×ULN for ≥7 days.

ALT or AST >3×ULN and either total bilirubin >2×ULN or INR >1.5, if INR 
measured.

ALT or AST >3×ULN with clinical indications of liver toxicity (signs, symptoms, or 
other diagnostic findings).

ALT or AST >5×ULN but <8×ULN and subject cannot be closely monitored as 
described below.
Subjects with potential signals of liver injury must be closely monitored as described below: 

Report the event to the  Sponsor’s medical monitor.

Repeat liver enzymes, total bilirubin, and INR at least twice weekly until liver 
function test elevations resolve or stabilize or the values return to baseline. (The 
frequency of retesting can decrease to once a week or less if abnormalities stabilize 
and the subject is asymptomatic.) 

Obtain a detailed history of symptoms, including any prior and concurrent diseases. 

Obtain a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol and recreational drug use, and 
any special diets consumed. 

Rule out acute viral hepatitis (types A, B, C, D, and E), autoimmune or alcoholic 
hepatitis, nonalcoholic steatohepatitis, hypoxic/ischemic hepatopathy, and biliary 
tract disease. 

Obtain a history of exposure to environmental chemical agents. 

Review additional tests to evaluate liver status, as appropriate. If alkaline phosphatase 
(ALP) is elevated, perform an analysis of ALP isoenzymes to determine if the origin 
of the ALP elevation is bone or liver. 

Consider scheduling the subject for gastroenterology or hepatology consultation. 

Collect ad hoc PK samples.
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Subjects who experience ALT or AST values >3× to <5×ULN, with total bilirubin <2×ULN and 
INR <1.5 (and have no clinical symptoms indicative of liver toxicity) may continue to receive 
study drug. However, ALT, AST, and total bilirubin tests should be repeated twice weekly until 
liver function test elevations resolve or stabilize or the values return to baseline. These repeat 
results will be discussed with the Sponsor’s medical monitor. If, at any time, the subject meets 
any of the above stopping criteria for potential liver injury, study drug treatment should be 
discontinued and the subject should be monitored as described above.
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APPENDIX 8.
DOSE MODIFICATION FOR DECREASE IN LEFT 
VENTRICULAR EJECTION FRACTION
Decreases of LVEF have been observed in patients receiving the MEK inhibitors trametinib
(Mekinist USPI) and cobimetinib (Cotellic USPI) and the ERK inhibitor GDC-0994 (Varga et al 
2020). ECHO or MUGA scans will be performed to assess cardiac ejection fraction in regular 
intervals as outlined in the schedule of events tables (Table 11 and Table 12).
Suggested guidelines regarding management and criteria for adjusting, withholding, and 
discontinuing study treatment for LVEF decrease are provided in Table 18. In the event that 
institutional standard practice differs from these suggested guidelines, institutional practices may 
be followed with best clinical judgement applied.
Table 18:
Suggested Action and Dose Modification for LVEF Decrease
LVEF Decrease (%)
Action and Dose Modification
Resting LVEF 49% to 40%; absolute 
decrease of >10% but <19% in LVEF 
from baseline and LVEF below the 
institution’s LLN

Interrupt study treatment and perform ECHO within 3 weeks.

If ECHO recovers within 3 weeks:

Consult with the  Sponsor’s medical monitor and request 
approval to restart ASTX029 dosing.

If approval is obtained, restart at a lower dose level.

If ASTX029 is restarted, repeat ECHO after 3, 6, and 9 weeks 
after restart; continue in intervals of every 12 weeks 
thereafter.

If ECHO does not recover within 3 weeks:

Consider cardiology consultation.

Permanently discontinue study treatment.

Repeat ECHO after 3, 6, and 9 weeks or until resolution or 
plateau.
Resting LVEF 39% to 20% or >20% 
absolute reduction from baseline

Inform the Sponsor’s medical monitor.

Permanently discontinue study treatment.
Resting LVEF <20%

Consult with a cardiologist.

Repeat ECHO after 3, 6, and 9 weeks or until resolution.
ECHO=echocardiogram; LVEF=left ventricular ejection fraction; LLN=lower limit of normal.
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APPENDIX 9.
MODIFICATIONS DURING THE COVID-19 HEALTH 
EMERGENCY
1.0 GENERAL INFORMATION
This section describes modifications to the study protocol to allow flexibility in conducting this 
study during the COVID-19 public health emergency while maintaining safety of trial 
participants, maintaining compliance with Good Clinical Practice (GCP), and minimizing risks 
to trial integrity. These modifications are intended to remain in effect only for the duration of the 
public health emergency related to COVID-19 and only in instances in which the study cannot be 
conducted per the protocol. 
Any modifications to the study protocol must be discussed with the Sponsor’s medical monitor 
before implementation.
2.0 STUDY STATUS
The feasibility of continuing this clinical study in the presence of the COVID-19 pandemic was 
assessed by the Sponsor to ensure subject safety and data integrity. The Sponsor decided to:

Continue to enroll/treat participants in this study with temporary modifications 
including:

Conversion of physical visits to telephone or video visits.

Modification to ensure that only strictly necessary visits are performed at study 
centers.

Allow laboratory test and/or diagnostic tests (excluding pharmacokinetic [PK] 
and biomarker analyses and disease assessments) to be conducted at a local 
laboratory, authorized certified to perform such tests, close to the subject’s 
residence, to reduce COVID-19 exposure, if needed.

Remote monitoring.

Remote source data verification (rSDV), where permitted by regulations.*

Changes to the informed consent process.*

Temporarily pause recruitment of new trial participants (at some study centers).

Extend the duration of the study, if needed, by 6 months.
* Where required, submitted as a substantial amendment.
3.0 COVID-19 BENEFIT/RISK ASSESSMENT
The safety of each trial participant is of primary importance, and the risks of participating in this 
clinical trial, given the challenges due to COVID-19, were carefully weighed against the 
anticipated benefit for trial participants. 
The Sponsor will reassess the risks of conducting this study as the situation develops and will 
document assessments as part of the sponsor’s trial master file. It is possible that local 
circumstances may lead to a local change in risk assessment (eg, an escalation of the pandemic 
within a certain region); therefore, the need to implement additional measures may arise. 
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Investigators may be asked to complete a risk assessment questionnaire or other document 
provided by the Sponsor(or designee. This assessment should be documented in the 
investigator’s site master file and communicated to the Sponsor. 
Benefits
The benefits of participating in this study during the COVID-19 pandemic include treatment of a 
life-threatening disease for which there are limited or no alternate therapies with new drugs or 
new drug combinations and include the added benefit of participating in a study with an oral 
formulation of the study drug administered for conditions for which only intravenous (IV) or 
subcutaneous therapy is available. 
Risks
Additional risks to participating in this trial during the COVID-19 pandemic may include: 

Visiting the study center may increase the risk of exposure to COVID-19, depending 
on the status of the pandemic in the area near the study center.

As a result of the disease and treatment, there may be risk of greater morbidity and 
mortality if COVID-19 is contracted. Additional measures implemented to mitigate 
this will depend on the individual study center.

In the event that, as a result of the pandemic, local health officials require shelter in 
place, alternative arrangements (eg, dosing at home on study days when study drug is 
to be taken in the clinic) may need to be made to assure subjects continue to receive 
treatment. Arrangements will be made in collaboration with each study center 
physician to minimize any such associated risks.
COVID-19 Benefit/Risk Summary
With the life-threatening nature of the condition being treated in this study and because there are 
no approved alternative treatments for such conditions, the potential anticipated benefits of 
continuation of this study justify the risks. Study centers will only be allowed to participate in 
this study during the COVID-19 outbreak if they are able to ensure they can monitor subject 
safety, ensure data integrity, and continue to oversee study conduct. 
4.0 MODIFICATIONS TO STUDY CONDUCT
4.1 Alternative Methods for Obtaining Informed Consent
Alternative methods for obtaining informed consent may be used for re-consenting subjects if 
necessary and must be appropriately documented in each subject’s chart. Alternative methods 
include, but are not limited to, contacting the subject via phone or video-calls and obtaining oral 
consent, supplemented with e-mail confirmation, as per Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) and Institutional policies or guidelines. 
4.2 Alternative Methods for Drug Supply
In extenuating circumstances (eg, during the COVID-19 pandemic) under which standard 
approaches to dispensing study drug to subjects are not possible, alternative methods for 
dispensing study drug to subjects may be used. The Sponsor will work with individual centers to 
find acceptable alternative arrangements (eg, shipment of study drug from study center 
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pharmacies to subjects) that assure compliant control of study drug and acceptable safety 
monitoring. Alternative methods for drug dispensing must be reviewed by the Sponsor before 
implementation.
4.3 Study Visits and Procedures 
Protocol-mandated visits and laboratory/diagnostic testing may be modified as follows: 

Telemedicine visits (ie, visits conducted via telephone and/or video, or in-person 
Telehealth visits with a health professional) may be permitted in lieu of in-person 
visits to monitor adverse events and participant safety. 

Telemedicine visits must be approved by the Sponsor and aligned with 
Institutional practice and local regulations.

Telemedicine visits must be appropriately documented in source documents.

Additional details regarding how to conduct telemedicine visits will be provided 
by the Sponsor. 
In-person visits are required to assess eligibility, perform baseline assessments, and for primary 
outcome measures. Telemedicine visits would generally not be permitted for the following 
visits/procedures unless approved by the Sponsor: 

Screening and/or predose Cycle 1 Day 1 (C1D1) assessments to determine eligibility.

Visits with mandatory fresh tumor sample collection and sample collection for 
biomarker and PK analyses. 

Visits with disease assessments (eg, computed tomography [CT], magnetic resonance 
imaging [MRI], tumor markers).

Visits with mandatory ophthalmic evaluations.

Day 1 cycle visits when a subject is in early cycles of the protocol-defined treatment.

Visits with investigator assessments of new serious or ≥Grade 3 adverse events (AEs) 
or suspected dose-limiting toxicity (DLT) events.
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APPENDIX 9: 
SUMMARY OF CHANGES FROM ORIGINAL VERSION IN 
AMENDMENT 1.0 
Protocol: ASTX029-01 
Amendment 1.0, Date: 21 February 2019 
Rationale for Amendment 1.0 
The protocol was amended to introduce the new tablet dosage form of ASTX029, increase the 
number of study centers, add Europe as a location of study centers for Phase 1, provide newly 
available nonclinical study results, and allow for administration of the powder-in-bottle (PiB) 
dosage form of ASTX029 by gastrostomy tube (g-tube). Time windows have been provided for 
certain assessments that are planned to occur at cycle visits to allow more scheduling flexibility 
for the subjects, investigators, and study centers without impacting subject safety. Additional 
minor editorial changes were made throughout for clarification and consistency. All changes in 
the body of the protocol are also reflected in the protocol synopsis, as applicable. 
Summary of Changes: 
1. 
A summary of a nonclinical pharmacokinetic study conducted in monkeys to support 
dosing of the tablet formulation in humans was added to the introduction (Section 1.3.2.1). 
2. 
A summary of nonclinical genotoxicity study results, which indicate no evidence of 
genotoxicity, was added to the introduction (Section 1.3.2.4). 
3. 
The numbers of study centers were increased to up to 14 for Phase 1 and to up to 30 for 
Phase 2, and Europe was added as a location of study centers for Phase 1 to facilitate 
enrollment and study completion in the Overall Study Design section (Section 4.1) and the 
Number of Subjects and Centers section (Section 5.1). 
4. 
Clarified the primary endpoint by adding details of how (by determining incidences of dose 
limiting toxicities and adverse events) the maximum tolerated dose (MTD) will be 
established (Section 4.3.1). 
5. 
Clarified that a subject who withdraws consent may request destruction of any untested 
samples and that this must be documented and reported to the sponsor within 24 hours in 
the Withdrawal From Study section (Section 5.4.2) and Tissue and Blood Sample 
Collection/Storage section (Section 14.2.5). 
6. 
Added details to Exclusion Criterion #4 for clarity (Section 5.3). 
7. 
The new ASTX029 tablet dosage form was added in multiple sections, including the Drug 
Substance, Drug Product, and Packaging section (Section 7.1.1), and the Transition from 
Powder-in-Bottle Dosage Form to Tablet Dosage Form section (Section 7.1.6) was added. 
8. 
Administration of the PiB dosage form of ASTX029 by g-tube was added as a dosing 
option to the Drug Substance, Drug Product, and Packaging section (Section 7.1.1). 


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9. 
Clarified that intrasubject escalations will not be allowed but that investigators may change 
subjects’ dose levels to the MTD or recommended dose for expansion (RDE) dose levels 
(once determined and with approval of Astex) in the Dose-Escalation Guidelines and 
Recommended Phase 2 Dose Decision section (Section 7.3). 
10. 
Clarified that tumor marker measurements are to be performed, if appropriate, as part of 
disease reassessments to assess response per Appendix 3, Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1, in multiple subsections in the Study Assessments and 
Procedures section (Section 9.0). 
11. 
To provide more flexibility for the subjects, investigators, and study centers and 
accommodate the time needed to obtain and review results from clinical laboratory 
assessment adjustments have been made in multiple subsections in the Study Assessments 
and Procedures section (Section 9.0). 
12. 
Added assessment of dosing compliance information for Regimen 1 Cycle 2 Days 8 and 
15 to correct an omission in study assessments and procedures sections (Section 9.4.9, 
Section 9.4.11.6, Section 9.4.11.7) and, for Regimen 2, moved the Cycle 2 Day 1 
assessment to Cycle 1 Day 14, the last dosing day of Cycle 1 for that regimen in study 
assessments and procedures sections (Section 9.4.9, Section 9.4.11.3, Section 9.4.11.5.1). 
13. 
Clarified that the Treatment Termination (Tx Term) visit is to occur within 3 days before 
starting new anticancer treatment (as applicable) and that, if a subject discontinues study 
treatment at a scheduled visit, that visit’s assessments can be used to fulfill the Tx Term 
visit requirements in the study assessments and procedures sections (Section 9.4.9, 
Section 9.4.13). 
14. 
The suggested actions and dose modifications for left ventricular ejection fraction (LVEF) 
decrease were clarified as being based on LVEF ranges rather than Common Terminology 
Criteria for Adverse Events in the Dose Modification for Decrease in Left Ventricular 
Ejection Fraction appendix (Appendix 8). 


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APPENDIX 9: 
SUMMARY OF CHANGES FROM AMENDMENT 1.0 TO 
AMENDMENT 2.0  
Protocol: ASTX029-01 
Amendment 2.0, Date: 12 July 2019 
Rationale for Amendment 2.0 
The protocol was amended to evaluate dosing of ASTX029 under fasting conditions in Phase 1 
Part A as a result of nonclinical data from 3 food-effect studies conducted in monkeys or dogs and 
preliminary clinical pharmacokinetic (PK) data becoming available. Additional minor editorial 
changes were made throughout for clarification and consistency. All changes in the body of the 
protocol are also reflected in the protocol synopsis, as applicable. 
Summary of Changes: 
1. 
Data from 3 food-effect studies conducted in monkeys or dogs were added to the 
Absorption, Distribution, Metabolism, and Excretion Studies and Nonclinical 
Pharmacokinetics section (Section 1.3.2.1). 
2. 
“Preliminary” was removed from the description of the data available from the in vitro 
chromosomal aberration assay in human peripheral blood lymphocytes in the Toxicology 
Studies section (Section 1.3.2.4) because the final report is now available. 
3. 
“Food effect on PK parameters” was added to the PK secondary objective in the Secondary 
Objectives section (Section 3.2) and to the PK secondary endpoint in the Secondary 
Endpoint(s) section (Section 4.3.2). 
4. 
Language regarding a potential food-effect cohort and a food-effect evaluation in Phase 1 
Part B was removed from multiple sections.  
5. 
A description of ASTX029 formulations (powder in bottle [PiB] and tablet) and 
administration conditions (fed and fasting) was added to the Overall Study Design section 
(Section 4.1, in place of the previous formulation descriptions), the Discussion of Study 
Design section (Section 4.2, along with the rationales for fed and fasted administration), 
and the ASTX029 Administration section (Section 7.1.5).  
6. 
The descriptions of the bottles of ASTX029 powder-in-bottle and of the vehicle for 
reconstitution as being “induction-sealed” and “150-mL induction-sealed,” respectively, 
were removed from the Drug Substance, Drug Product, and Packaging section (Section 
7.1.1). 
7. 
Administration of ASTX029 under fasted conditions was specified as being introduced 
with Amendment 2 the ASTX029 Administration section (Section 7.1.5). 
8. 
The Transition From Fed to Fasted Administration section (Section 7.1.7, in which DLT 
and PK data as of this amendment and fasted-dose administration are described) was added. 


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9. 
“With a known risk of torsades de pointes while on study treatment” was added in the 
Prohibited Medications and Substances section (Section 7.6.2) to the description of QT 
interval corrected for heart rate (QTc)-prolonging medications of which potential 
concomitant use is to be discussed with Astex Pharmaceutical’s medical monitor. 
10. 
The specification that the Cycle 1 Day 1 electrocardiogram results must meet study entry 
criteria before ASTX029 dosing was added within Section 9.4 subsections, including 
Table 9 and Table 10 footnotes.  
11. 
Discussion of administration of ASTX029 with food, still present in Drug Administration 
Under Fed Conditions subsection of the ASTX029 Administration section (Section 7.1.5), 
was removed from the Treatment and Follow-up Procedures section (Section 9.4.11).  


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APPENDIX 9: 
SUMMARY OF CHANGES FROM AMENDMENT 2.0 TO 
AMENDMENT 3.0 
Protocol: ASTX029-01 
Amendment 3.0, Date: 31 December 2019 
Rationale for Amendment 3.0 
The protocol was amended to modify Phase 2 cohorts and specify Phase 2 evaluations in 
preparation for initiation of Phase 2 and to remove ASTX029 tablet strength information to 
accommodate potential additional strengths, which are to be specified in the Investigator Brochure 
(IB). Additional minor editorial changes were made throughout for clarification and consistency. 
All changes in the body of the protocol are also reflected in the protocol synopsis, as applicable. 
Summary of Changes: 
1. 
The numbers of subjects in Phases 1 and 2 were adjusted per updated estimates (Section 
4.1 and Section 5.1). 
2. 
The Phase 2 cohorts for B isoform of RAF kinase (BRAF)-fusion cancers (Cohort D) and 
gynecological cancers with alterations in the mitogen-activated protein kinase (MAPK) 
pathway (Cohort E) were added; 2 previously specified cohorts (Cohort B and Cohort C) 
were modified; and the cohort for tumors with other gene alterations (previously Cohort 
D) was designated as Cohort F (Figure 2, Section 4.1; Section 4.1.2; Section 5.1; and 
Section 11.1). 
3. 
ASTX029 tablet strength information was replaced with a reference to the current 
ASTX029 IB (Section 7.1.1). 
4. 
Dosing information at the time of Amendment 2 was replaced with the fact that Phase 1 
Part A dose escalation is ongoing under the fasted condition at the time of Amendment 3.0 
(Section 7.1.7). 
5. 
Pharmacokinetic assessments during Phase 2 were specified (Table 6 and Table 7, 
Section 9.2.1). 
6. 
Biomarker assessments and tumor biopsies during Phase 2 were specified (Table 6 and 
Table 9, respectively, Section 9.2.2; Table 11 and Table 12, Section 9.4.9; and subsequent 
Section 9.4 subsections). 
7. 
Other Phase 2 evaluations were specified (Table 11 and Table 12, Section 9.4.9 and 
subsequent Section 9.4 subsections). 
8. 
Study visit windows were specified (Table 11 and Table 12, Section 9.4.9). 


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APPENDIX 9: 
SUMMARY OF CHANGES FROM AMENDMENT 3.0 TO 
AMENDMENT 4.0  
Protocol: ASTX029-01 
Amendment 4.0, Date: 21 July 2020 
Rationale for Amendment 4.0 
The protocol was amended to add language regarding conducting the study during the COVID-19 
pandemic to enable continuation of the study during the pandemic, clarify that Regimen 2 may not 
need to be evaluated during Phase 1 Part A to determine the regimen to be evaluated in Phase 1 
Part B, specify contraceptive use and pregnancy tests consistent with requirements of countries 
other than the United States (US) as well as the US, remove descriptions of the phased out 
ASTX029 powder-in-bottle [PiB] formulation or change the descriptions to the past tense. 
Additional minor editorial changes were made throughout for clarification and consistency. All 
changes in the body of the protocol are also reflected in the protocol synopsis, as applicable. 
Summary of Changes: 
1. 
Updated the medical monitor information. 
2. 
Clarified that Regimen 2 may not need to be evaluated during Phase 1 Part A to determine 
the regimen to be evaluated in Phase 1 Part B. 
3. 
Extended the expected duration of recruitment for the study by 6 months. 
4. 
Changed contraceptive use specifics for women of childbearing potential and men. 
5. 
Added language about sperm donation for men and egg (ova, oocyte) donation for women 
of childbearing potential. 
6. 
Added a pregnancy test within 24 hours before the start of ASTX029 on Day 1 of Cycle 1 
and specified that pregnancy tests before Cycles 2 through 6 are to be done within 24 hours 
before the start of treatment for those cycles. 
7. 
Indicated the PiB dosage form was phased out and changed the descriptions of PiB dosing 
to the past tense. 
8. 
Clarified that grapefruit juice is not allowed during treatment with ASTX029 rather than 
during subjects’ participation in the study. 
9. 
Added language regarding conducting the study during the COVID-19 pandemic. 

SAP_001.pdf: 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 4 4 of 4 6
2 A pril 2 0 2 4
S T A TI S TI C A L A N A L Y SI S P L A N
V E R SI O N: v 0. 1
D A T E O F P L A N: 2 A P R 2 0 2 4
S T U D Y D R U G:
A S T X 0 2 9
P R O T O C O L N U M B E R:
A S T X 0 2 9- 0 1
S T U D Y TI T L E:
A P h ase 1- 2 St u d y of t he S afet y, P h ar m ac o ki netics, a n d Acti vit y of A S T X 0 2 9 i n S u bjects wit h 
A d v a nce d S oli d T u m ors
S P O N S O R:
Tai h o O nc ol o g y, I nc.
1 0 1 Car ne gie Ce nter
Pri ncet o n, NJ U S A 0 8 5 4 0
+ 1 ( 6 0 9) 7 5 0- 5 3 0 0
T his trial was c o n d ucte d i n acc or da nce wit h t he et hical pri nci ples of G o o d Cli nical Practice 
( G C P), acc or di n g t o t he I nter nati o nal C o nfere nce o n Har m o nizati o n (I C H) Har m o nize d 
Tri partite G ui deli ne.
C o nfi de nti alit y St ate me nt
T he i nf or mati o n i n t his d oc u me nt c o ntai ns tra de secrets a n d c o m mercial i nf or mati o n t hat are privile ge d or 
c o nfi de nti al a n d ma y n ot be discl ose d u nless s uc h discl os ure is re q uire d b y a p plica ble la w or re g ulati o ns. 
I n a n y e ve nt, pers o ns t o w h o m t he i nf or mati o n is discl ose d m ust be i nf or me d t hat t he i nf or mati o n is privile ge d or 
c o nfi de nti al a n d ma y n ot be f urt her discl ose d b y t he m.  T hese restricti o ns o n discl os ure will a p pl y e q uall y t o all 
f ut ure i nf or mati o n s u p plie d t o y o u t hat is i n dicate d as privile ge d or c o nfi de nti al .


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 4 5 of 4 6
2 A pril 2 0 2 4
SI G N A T U R E S
A U T H O R E D B Y:
M A, J D
 Bi ostatistics 
A P P R O V E D B Y:
 M D 
St u d y Direct or
P h D
 Bi ostatistics 
M D, P h D


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 4 6 of 4 6
2 A pril 2 0 2 4
T A B L E O F C O N T E N T S 
SI G N A T U R E S ............................................................................................................................. 4 5
V E R SI O N HI S T O R Y.................................................................................................................. 4 8
A B B R E VI A TI O N S A N D D E FI NI TI O N S................................................................................. 4 9
1. 0 
I N T R O D U C TI O N ........................................................................................................... 5 1
1. 1 
Bac k gr o u n d............................................................................................................ 5 1
1. 2 
Treat me nt O pti o n................................................................................................... 5 1
1. 2. 1  
A S T X 0 2 9.............................................................................................. 5 2
2. 0 
S T U D Y O B J E C TI V E S.................................................................................................... 5 2
2. 1 
Pri mar y O bjecti ve.................................................................................................. 5 2
2. 2 
Sec o n dar y O bjecti ves............................................................................................. 5 2
2. 3 
E x pl orat or y O bjecti ves.......................................................................................... 5 3
3. 0 
S T U D Y D E SI G N.............................................................................................................. 5 3
3. 1  
O verall St u d y Desi g n............................................................................................. 5 3
3. 2 
St u d y E n d p oi nts..................................................................................................... 5 5
3. 2. 1 
Pri mar y E n d p oi nt.................................................................................. 5 5
3. 2. 2 
Sec o n dar y E n d p oi nts............................................................................. 5 5
3. 2. 3 
E x pl orat or y E n d p oi nts .......................................................................... 5 5
4. 0 
S A M P L E SI Z E................................................................................................................. 5 5
5. 0  
A N A L Y SI S S E T S ............................................................................................................ 5 6
6. 0 
S C H E D U L E O F A N A L Y S E S......................................................................................... 5 7
7. 0 
S T A TI S TI C A L A N A L Y SI S ........................................................................................... 5 7
7. 1 
S u bject Dis p ositi o n................................................................................................ 5 9
7. 2  
De m o gra p hic a n d Ot her Baseli ne C haracteristics ................................................. 5 9
7. 3 
P har mac o ki netics A nal yses ................................................................................... 5 9
7. 4 
P har mac o d y na mic A nal yses.................................................................................. 6 0
7. 5 
Efficac y Varia bles a n d A nal yses........................................................................... 6 0
7. 6 
Safet y Varia bles a n d A nal yses............................................................................... 6 3
7. 6. 1 
St u d y Treat me nt a n d E x p os ure............................................................. 6 3
7. 6. 2  
A d verse E ve nts ..................................................................................... 6 3
7. 6. 3  
D ose Li miti n g T o xicities ...................................................................... 6 4
7. 6. 4  
All-ca use M ortalit y............................................................................... 6 4
7. 6. 5 
C o nc o mita nt Me dicati o ns..................................................................... 6 5
7. 6. 6 
La b orat or y Tests ................................................................................... 6 5
7. 6. 7  
Vital Si g ns............................................................................................. 6 5


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 4 7 of 4 6
2 A pril 2 0 2 4
7. 6. 8 
Electr ocar di o gra m ( E C G)..................................................................... 6 6
7. 6. 9 
E C O G Perf or ma nce Stat us.................................................................... 6 6
7. 6. 1 0 
Ec h ocar di o gra m / M ulti gate d Ac q uisiti o n ( E C H O/ M U G A)................ 6 6
7. 6. 1 1 
P h ysical E xa mi nati o n............................................................................ 6 6
7. 7  
Ha n dli n g of Missi n g Data a n d Ot her Data A n o malies.......................................... 6 6
7. 8  
Ha n dli n g of Pr ot oc ol De viati o ns ........................................................................... 6 6
8. 0 
S U P P O R TI N G D O C U M E N T A TI O N ........................................................................... 6 7
8. 2  
A p pe n di x 3: S u m mar y of C ha n ges........................................................................ 6 7
9. 0  
R E F E R E N C E S................................................................................................................. 6 8
LI S T O F T A B L E S
Ta ble 1: 
S u m mar y of O verall Assess me nt of Res p o nse.......................................... 6 1
LI S T O F FI G U R E S
N o t a ble of fi g ures e ntries f o u n d.


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 4 8 of 4 6
2 A pril 2 0 2 4
V E R SI O N HI S T O R Y
S A P Versi o n
A p pr o v al D ate
C h a n ge
R ati o n ale
V 1. 0
2 A pr 2 0 2 4
Ori gi n al


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 4 9 of 4 6
2 A pril 2 0 2 4
A B B R E VI A TI O N S A N D D E FI NI TI O N S
A Da M 
a nal ysis data m o del
A E 
  
a d verse e ve nt
A L K 
a na plastic l y m p h o ma ki nase
A T C  
A nat o mical T hera pe utic C he mical
A U C  
area u n der t he c ur ve
B D M 
Bi ostatistics a n d Data Ma na ge me nt
b p m 
beats per mi n ute
B R A F  
B is of or m of R A F ki nase
C DI S C 
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m
CI  
c o nfi de nce i nter val
C ma x   
ma xi m u m c o nce ntrati o n
C mi n   
mi ni m u m c o nce ntrati o n
C R 
c o m plete res p o nse
C R C  
c ol orectal ca ncer
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
ct D N A  
circ ulati n g t u m or D N A
C x D x  
C ycle x Da y x
D C R  
disease c o ntr ol rate
D L T  
d ose-li miti n g t o xicit y
D N A 
de o x yri b o n ucleic aci d
D O R 
d urati o n of res p o nse
D S R C  
Data a n d Safet y Re vie w C o m mittee
E C G  
electr ocar di o gra m
E C H O  
ec h ocar di o gra m
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p
e C R F               electr o nic case re p ort f or m
E G F R  
e pi der mal gr o wt h fact or rece pt or
E R K  
e xtracell ular si g nal-re g ulate d ki nase
FI H  
first-i n- h u ma n
H R A S  
Har ve y R A S
I B  
I n vesti gat or Br oc h ure
I C F  
i nf or me d c o nse nt f or m
I D  
i de ntificati o n
I V  
i ntra ve n o us
K R A S  
Kirste n R A S
m  
mi n ute(s)
m m  
milli meter
m m H g  
milli meters of merc ur y
M A P K  
mit o ge n-acti vate d pr otei n ki nase
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M E K  
mit o ge n-acti vate d e xtracell ular si g nal-re g ulate d ki nase
M T D  
ma xi m u m t olerate d d ose
M U G A  
m ulti ple- gate d ac q uisiti o n
N R A S  
ne ur o blast o ma R A S


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 0 of 4 6
2 A pril 2 0 2 4
O R R 
o verall res p o nse rate
O S 
o verall s ur vi val
P A P 
P har mac o ki netic A nal ysis Pla n
P D 
pr o gressi ve disease
P F S 
pr o gressi o n-free s ur vi val
P K 
p har mac o ki netic(s)
P R 
partial res p o nse
p R S K 
p h os p h or ylate d ri b os o mal s 6 ki nase
P T 
Preferre d Ter m
Q Tc  
Q T i nter val c orrecte d f or heart rate
Q Tc F  
Q Tc c orrecte d f or heart rate usi n g Fri dericia’s f or m ula
R A F 
ra pi dl y accelerate d fi br osarc o ma
R D E 
rec o m me n de d d ose f or e x pa nsi o n
R E CI S T 
Res p o nse E val uati o n Criteria i n S oli d T u m ors
R P 2 D 
rec o m me n de d P hase 2 d ose
S A E 
seri o us a d verse e ve nt
S A P 
Statistical A nal ysis Pla n
S D 
sta ble disease
S D T M 
St u d y Data Ta b ulati o n M o del
S O C 
S yste m Or ga n Class
t ½ 
eli mi nati o n half-life
T E A E 
treat me nt-e mer ge nt a d verse e ve nt
T ma x
ma xi m u m c o nce ntrati o n
W H O  
W orl d Healt h Or ga nizati o n


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 1 of 4 6
2 A pril 2 0 2 4
1. 0 
I N T R O D U C TI O N
T he p ur p ose of t his d oc u me nt is t o pr o vi de details of t he pla n ne d a nal yses f or t he P hase 1 a n d 2 
A S T X 0 2 9- 0 1 st u d y. T he st u d y is t o assess t he safet y, P K, p har mac o d y na mics, a n d preli mi nar y 
cli nical acti vit y of A S T X 0 2 9 a d mi nistere d orall y t o s u bjects ≥1 8  years of a ge wit h a d va nce d s oli d 
mali g na ncies w h o are n ot ca n di dates f or a p pr o ve d or a vaila ble t hera pies. 
T he pri mar y o bjecti ves of t he P hase 1 p orti o n of t his st u d y are t o assess safet y a n d t o i de ntif y t he 
M T D, t he R P 2 D, a n d t he rec o m me n de d d osi n g re gi me n of A S T X 0 2 9 a d mi nistere d orall y. T he 
pri mar y o bjecti ve of t he P hase 2 p orti o n of t his st u d y is t o assess preli mi nar y cli nical acti vit y, as 
deter mi ne d b y o bjecti ve res p o nse rate ( O R R) i n t u m ors c haracterize d b y ge ne a berrati o ns i n t he 
M A P K si g nal pat h wa y t hat ma y c o nfer se nsiti vit y t o A S T X 0 2 9.
T he a nal yses s pecifie d i n t his d oc u me nt s u perse de t he hi g h-le vel a nal ysis pla n descri be d i n t he 
pr ot oc ol. A nal yses a n d statistical re p orti n g f or A S T X 0 2 9- 0 1 s u bjects, wit h t he e xce pti o n of t he 
a nal yses t hat are descri be d i n a se parate P har mac o metrics A nal ysis Pla n ( P A P), will be c o n d ucte d 
b y Tai h o O nc ol o g y Bi ostatistics de part me nt usi n g S A S versi o n 9. 4 or hi g her.
T his Statistical A nal ysis Pla n ( S A P) is base d o n t he A S T X 0 2 9- 0 1 pr ot oc ol a me n d me nt 5. 0 
( date d 1 4 A pril 2 0 2 2). 
S pecificati o ns f or data ta bles, listi n gs a n d fi g ures are detaile d i n a se parate d oc u me nt.
1. 1 
B ac k gr o u n d
Hist oricall y, me dical a p pr oac hes t o treat a d va nce d mali g na ncies ha ve t y picall y i n v ol ve d s ur ger y, 
ra di ot hera p y, a n d/ or c yt ot o xic c he m ot hera p y. A d va nces i n ge n o mics a n d m olec ular bi ol o g y ha ve 
le d t o s uccessf ul de vel o p me nt of t hera pies tar geti n g s pecific dri ver m utati o ns i n ca ncer cells (e. g., 
e pi der mal gr o wt h fact or rece pt or [ E G F R], B is of or m of R A F ki nase [ B R A F], A L K, B C R- A B L, 
KI T) ( Frie d ma n et al 2 0 1 5; X u et al 2 0 1 4 ). M ore rece ntl y, ca ncer i m m u n ot hera p y has als o bee n 
s h o w n t o si g nifica ntl y i m pr o ve t he o utc o mes of ma n y ca ncers. H o we ver, a si g nifica nt pr o p orti o n 
of patie nts e ve nt uall y rela pse d ue t o ac q uire d resista nce, a n d ot hers prese nt i ntri nsic resista nce 
mec ha nis ms ( Far k o na et al., 2 0 1 6 ). T h us, t here is a n u n met nee d f or ne w a p pr oac hes t o st o p t he 
u nc o ntr olle d gr o wt h of ca ncer .
1. 2 
Tre at me nt O pti o n 
Tar geti n g t he M A P K pat h wa y has bee n cli nicall y vali date d b y B R A F i n hi bit ors (e. g., ve m urafe ni b 
a n d  
da brafe ni b)  
a n d  
M E K  
i n hi bit ors  
(e. g.,  
tra meti ni b  
a n d  
c o bi meti ni b) 
( htt ps:// w w w.access data.f da. g o v/scri pts/c der/ daf/). 
T hese a ge nts elicit pr of o u n d a ntit u m or 
res p o nses i n B R A F V 6 0 0 E- m uta nt mela n o ma patie nts, alt h o u g h res p o nses are ofte n s h ort-li ve d, 
d ue t o t he o nset of ac q uire d dr u g resista nce ( Fla hert y et al 2 0 1 2; Ha usc hil d et al 2 0 1 2; Little et al 
2 0 1 2; C ha p ma n et al 2 0 1 1; S olit a n d R ose n 2 0 1 1 ). A c o m m o n feat ure of R A F or M E K i n hi bit or 
resista nce mec ha nis ms is t he reacti vati o n of E R K si g nali n g, w hic h dri ves pr oliferati o n a n d 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 2 of 4 6
2 A pril 2 0 2 4
s ur vi val of t he cells, e ve n i n t he prese nce of B R A F a n d M E K i n hi bit ors (Little et al 2 0 1 2; Wa gle 
et al 2 0 1 1; Nazaria n et al 2 0 1 0; E mer y et al 2 0 0 9 ). As E R K is t he pri mar y d o w nstrea m effect or of 
t he M A P K pat h wa y, it is h y p ot hesize d t hat E R K i n hi bit ors ma y pr o ve t o be less s usce pti ble t o 
o nc o ge nic b y pass t ha n R A F a n d M E K i n hi bit ors a n d, t heref ore, ha ve t he p ote ntial t o i m pr o ve 
cli nical o utc o mes i n t hese patie nt p o p ulati o ns ( Nissa n et al 2 0 1 3 ). 
Se veral E R K i n hi bit ors ha ve rece ntl y e ntere d cli nical de vel o p me nt, alt h o u g h n o ne ha ve gai ne d 
re g ulat or y a p pr o val yet. E R K i n hi bit ors i n cli nical de vel o p me nt i ncl u de G D C- 0 9 9 4 ( Ge ne ntec h; 
oral r o ute), uli xerti ni b ( Bi o Me d Valle y; oral r o ute), L Y 3 2 1 4 9 9 6 ( Eli Lill y; oral r o ute), C C- 9 0 0 0 3 
( Cel ge ne; oral r o ute), L T T 4 6 2 ( N o vartis; oral r o ute), K O- 9 4 7 ( K ura O nc ol o g y; i ntra ve n o us [I V] 
r o ute), a n d 
M K- 8 3 5 3 ( Merc k S har p & D o h me C or p; oral r o ute) ( htt ps://cli nicaltrials. g o v/). 
N ota bl y, i n t he P hase 1 st u d y of G D C- 0 9 9 4 (a n E R K 1/ 2 i n hi bit or), partial res p o nses were o bser ve d 
i n 2 s u bjects wit h B R A F m uta nt C R C (Var ga et al a bstract 2 0 1 6; Var ga et al prese ntati o n 2 0 1 6 ). 
Res p o nses were als o o bser ve d i n s u bjects wit h B R A F a n d N R A S m utati o ns e nr olle d i n a P hase 
1- 2 st u d y of uli xerti ni b ( S ulli va n et al 2 0 1 8; Li et al prese ntati o n 2 0 1 7; I nfa nte et al a bstract 2 0 1 5; 
I nfa nte et al prese ntati o n 2 0 1 5). 
1. 2. 1  
A S T X 0 2 9
A S T X 0 2 9 is a s y nt hetic s mall m olec ule t hat was de vel o pe d usi n g Tai h o’s fra g me nt- base d dr u g 
disc o ver y platf or m. U nli ke m ost E R K i n hi bit ors c urre ntl y i n t he cli nic, A S T X 0 2 9 b ot h pre ve nts 
t he p h os p h or ylati o n of E R K a n d directl y i n hi bits E R K ki nase acti vit y, w hic h is e x pecte d t o 
pr o d uce a m ore effecti ve bl oc ki n g of t he M A P K pat h wa y. F or detail i nf or mati o n o n A S T X 0 2 9, 
refer t o t he c urre nt A S T X 0 2 9 I n vesti gat or Br oc h ure (I B) Secti o n 4. 1. 
2. 0 
S T U D Y O B J E C TI V E S
2. 1 
Pri m ar y O bjecti ve

P hase 1 ( Parts A a n d B): T o assess safet y a n d t o i de ntif y t he M T D, t he R P 2 D, a n d t he 
rec o m me n de d d osi n g re gi me n of A S T X 0 2 9.

P hase 2: T o assess preli mi nar y cli nical acti vit y, as deter mi ne d b y O R R, i n t u m ors c haracterize d 
b y ge ne a berrati o ns i n t he M A P K si g nal pat h wa y t hat ma y c o nfer se nsiti vit y t o A S T X 0 2 9.
2. 2 
Sec o n d ar y O bjecti ves 

T o deter mi ne t he P K pr ofile of A S T X 0 2 9 i ncl u di n g t he f o o d effect o n P K para meters.

T o e val uate ot her cli nical acti vit y para meters, s uc h as d urati o n of res p o nse ( D O R), disease 
c o ntr ol rate ( D C R), pr o gressi o n-free s ur vi val ( P F S), a n d o verall s ur vi val ( O S).

T o e val uate rele va nt p har mac o d y na mic mar kers a n d tar get e n ga ge me nt (i.e., p h os p h or ylate d 
ri b os o mal s 6 ki nase [ p R S K] i n hi biti o n) i n t u m or bi o psies.


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 3 of 4 6
2 A pril 2 0 2 4
2. 3 
E x pl or at or y O bjecti ves 

T o i de ntif y a n d e val uate bi o mar kers of A S T X 0 2 9 acti vit y.
3. 0 
S T U D Y D E SI G N
3. 1  
O ver all St u d y Desi g n
T his is a first-i n- h u ma n ( FI H), o pe n-la bel, m ultice nter, P hase 1- 2 st u d y t o assess t he safet y of 
A S T X 0 2 9, deter mi ne t he M T D, R P 2 D, a n d rec o m me n de d d osi n g re gi me n f or A S T X 0 2 9, a n d t o 
o btai n preli mi nar y cli nical acti vit y, P K, a n d p har mac o d y na mic data i n s u bjects wit h a d va nce d 
s oli d t u m ors f or w h o m sta n dar d life- pr ol o n gi n g meas ures or a p pr o ve d t hera pies are n ot a vaila ble. 
It is a ntici pate d t hat u p t o 3 0 0 e val ua ble s u bjects will be e nr olle d i n t his st u d y if t he st u d y f ull y 
e nr olls b ot h P hases 1 a n d 2. T his i ncl u des a p pr o xi matel y 1 2 0 s u bjects i n P hase 1 at u p t o 1 4 st u d y 
ce nters i n t he U S a n d E ur o pe a n d u p t o a p pr o xi matel y 1 8 0 e val ua ble s u bjects i n P hase 2 at u p t o 
3 0 st u d y ce nters i n N ort h A merica a n d E ur o pe. T he e x pecte d st u d y d urati o n is a p pr o xi matel y 3. 5 
years ( 4 2 m o nt hs), i ncl u di n g a p pr o xi matel y 3 6 m o nt hs f or recr uit me nt a n d a p pr o xi matel y 6 
m o nt hs f or safet y f oll o w- u p. 
T his st u d y c o nsists of 2 p hases, as s h o w n i n t he st u d y sc he ma bel o w ( Fi g ure 1).
Fi g ure 1:  
St u d y Sc he m a 
B R A F = B is of or m of R A F ki nase;  FI H =first-i n- h u ma n; M T D = ma xi m u m t olerate d d ose; R A S =rat sarc o ma vir us; 
Q D = dail y; R D E =rec o m me n de d d ose f or e x pa nsi o n; R P 2 D =rec o m me n de d P hase 2 d ose.   
N ote: T he R P 2 D a n d rec o m me n de d d osi n g re gi me n will be use d i n P hase 2 as i n dicate d b y arr o w.
T he P hase 1 p orti o n of t he st u d y c o nsists of Parts A ( D ose Escalati o n) a n d B ( D ose E x pa nsi o n). 
Part A is a d ose-escalati o n sta ge t o i de ntif y t he M T D f or u p t o 2 d osi n g re gi me ns of A S T X 0 2 9 
a n d t he rec o m me n de d d ose f or e x pa nsi o n ( R D E), defi ne d as eit her t he M T D or a d ose bel o w M T D 
t hat t he Data a n d Safet y Re vie w C o m mittee ( D S R C) a grees s h o ws a de q uate safet y, P K, a n d/ or 
preli mi nar y bi ol o gical or cli nical acti vit y. S u bjects e nr olle d i n Re gi me n 1 (c o nti n u o us d osi n g) 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 4 of 4 6
2 A pril 2 0 2 4
recei ve A S T X 0 2 9 orall y o nce a da y o n Da ys 1 t hr o u g h 2 1 of eac h 2 1- da y c ycle. If Re gi me n 2 
(i nter mitte nt d osi n g) is o pe ne d t o e nr oll me nt, s u bjects e nr olle d i n Re gi me n 2 will recei ve 
A S T X 0 2 9 orall y o nce a da y o n Da ys 1 t hr o u g h 1 4 of eac h 2 1- da y c ycle. I nitiall y, s u bjects will be 
all ocate d t o Re gi me n 1 (c o nti n u o us d osi n g). T he s p o ns or, wit h a p pr o val of t he D S R C, will 
deter mi ne if Re gi me n 2 is t o be o pe ne d f or e nr oll me nt. Ra n d o mizati o n t o eit her Re gi me n 1 or 
Re gi me n 2 will be gi n if b ot h re gi me ns are o pe n f or e nr oll me nt. If t he M T D is reac he d i n 1 re gi me n 
bef ore t he ot her re gi me n, all s u bse q ue nt s u bjects will be e nr olle d, wit h o ut ra n d o mizati o n, t o t he 
re mai ni n g re gi me n u ntil t he M T D is deter mi ne d f or eac h re gi me n e val uate d. 
T he starti n g d ose i n Re gi me n 1 will be escalate d ste p wise i n s uccessi ve c o h orts of at least 3 
e val ua ble s u bjects eac h wit h a d diti o nal all o we d e x pa nsi o n t o 6 s u bjects ( 3 + 3 st u d y desi g n) u ntil 
t he M T D is deter mi ne d f or t he re gi me n. D ose le vels a n d d osi n g re gi me ns, t he n u m ber of c o h orts, 
a n d t he n u m ber of s u bjects per c o h ort ma y be m o difie d, as nee de d, i n res p o nse t o e mer gi n g data 
a n d rec o m me n dati o ns fr o m t he D S R C. 
D ose-escalati o n/ de-escalati o n decisi o ns will be base d o n t he occ urre nce of d ose-li miti n g t o xicities 
( D L Ts) d uri n g t he first c ycle of eac h d ose le vel a n d t he rec o m me n dati o ns of t he D S R C f oll o wi n g 
re vie w of all a vaila ble safet y, P K, a n d bi o mar ker data fr o m t he c o m plete d first c ycle of at least 3 
s u bjects i n eac h c o h ort. T he D S R C R D E decisi o n will be base d o n all a vaila ble safet y, P K, 
bi o mar kers, a n d preli mi nar y acti vit y data fr o m all c ycles (i ncl u di n g p ote ntial f or late or c u m ulati ve 
t o xicit y). T he D S R C will als o a d vise w het her it is a p pr o priate t o pr ocee d t o Part B ( D ose 
E x pa nsi o n). 
I n Part B, o ne or m ore d ose le vels (a n d re gi me ns) ma y be st u die d t o s u p ple me nt a vaila ble safet y, 
P K, a n d/ or cli nical acti vit y data a n d t o e val uate tar get e n ga ge me nt i n fres h t u m or tiss ue bi o psies. 
A t otal of 1 4 e val ua ble s u bjects will be treate d at eac h d ose/re gi me n selecte d. If m ore t ha n 1 
d ose/re gi me n is selecte d, s u bjects will be ra n d o mize d i n a 1: 1 rati o. S u bjects will ha ve t o meet t he 
f oll o wi n g m olec ular eli gi bilit y criteria: d oc u me nte d acti vati n g ge ne m utati o ns i n B R A F ( B R A F 
V 6 0 0 m utati o n or acti vati n g at y pical n o n- V 6 0 0 a berrati o ns), Kirste n R A S ( K R A S), N R A S, or 
Har ve y R A S ( H R A S). T he R P 2 D decisi o n b y t he D S R C will be base d o n all a vaila ble P K, 
p har mac o d y na mic, safet y, a n d preli mi nar y acti vit y data fr o m all c ycles (i ncl u di n g t he p ote ntial f or 
late or c u m ulati ve t o xicit y). T he R P 2 D c o ul d be t he sa me or l o wer t ha n t he R D E. 
 
T he D S R C will a d vise w he n it is a p pr o priate t o pr ocee d t o P hase 2. T he P hase 2 p orti o n of t he 
st u d y will e x pl ore t he preli mi nar y si n gle-a ge nt a ntit u m or acti vit y of A S T X 0 2 9 at t he R P 2 D of 
t he selecte d d osi n g re gi me n i de ntifie d i n P hase 1 Parts A a n d B i n t u m ors c haracterize d b y ge ne 
a berrati o ns i n t he M A P K si g nal pat h wa y t hat ma y c o nfer se nsiti vit y t o A S T X 0 2 9. T he P hase 2 
part of t he st u d y will c o nsist of t he f oll o wi n g 6 c o h orts: 
•
C o h ort A: N R A S- m uta nt mela n o ma. 
•
C o h ort B: K R A S- m uta nt or K R A S-a m plifie d n o n-s mall cell l u n g ca ncer ( N S C L C). 
•
C o h ort C: B R A F V 6 0 0- m uta nt ca ncers ( n o n-c ol orectal ca ncers). 
•
C o h ort D: B R A F-f usi o n ca ncers.  


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 5 of 4 6
2 A pril 2 0 2 4
•
C o h ort E: G y nec ol o gical ca ncers wit h alterati o ns i n t he M A P K pat h wa y. 
•
C o h ort F: T u m ors c haracterize d b y ot her ge ne a berrati o ns t hat u pre g ulate t he M A P K 
si g nal pat h wa y. I n t he P hase 2 part of t he st u d y, m olec ular eli gi bilit y will be base d o n t he prese nce 
of d oc u me nte d ge ne a berrati o ns i n M A P K pat h wa y.  
F or P hase 2, t he sa m ple size is base d o n a Si m o n’s O pti mal 2-sta ge desi g n. Eac h c o h ort will 
e nr oll 1 0 s u bjects i nt o t he first sta ge of Si m o n’s 2-sta ge desi g n at t he R P 2 D a n d t he d osi n g 
re gi me n i de ntifie d i n P hase 1 Parts A a n d B. S h o ul d ≥2 first-sta ge s u bjects res p o n d, a n 
a d diti o nal 1 9 s u bjects will be e nr olle d i nt o t he sec o n d sta ge. T heref ore, u p t o 2 9 s u bjects will be 
e nr olle d i nt o eac h c o h ort.  
3. 2 
St u d y E n d p oi nts 
3. 2. 1 
Pri m ar y E n d p oi nt 

P hase 1: I nci de nces of D L Ts a n d a d verse e ve nts ( A Es) t o deter mi ne t he M T D of u p t o 2 d osi n g 
re gi me ns of A S T X 0 2 9 a n d t he R P 2 D a n d re gi me n t o be ta ke n t o P hase 2.  

P hase 2: Cli nical acti vit y assesse d b y O R R acc or di n g t o R E CI S T v 1. 1 criteria.
3. 2. 2 
Sec o n d ar y E n d p oi nts

P K para meters of A S T X 0 2 9, i ncl u di n g area u n der t he c ur ve ( A U C), ma xi m u m c o nce ntrati o n 
( C ma x), mi ni m u m c o nce ntrati o n ( C mi n), ti me t o reac h ma xi m u m c o nce ntrati o n ( T ma x), 
eli mi nati o n half-life (t ½), f o o d effect o n A S T X 0 2 9 P K para meters, a n d ot her sec o n dar y P K 
para meters of A S T X 0 2 9 if data per mit; a nal ysis of A S T X 0 2 9 meta b olites if a p plica ble.  

I n hi biti o n of p R S K pr otei n i n res p o nse t o A S T X 0 2 9 treat me nt i n t u m or bi o psies. 

Pr o gressi o n-free S ur vi val ( P F S). 

O verall S ur vi val ( O S). 

Disease C o ntr ol Rate ( D C R). 

D urati o n of Res p o nse ( D O R). 
3. 2. 3 
E x pl or at or y E n d p oi nts

S u p pressi o n of m uta nt cl o nes i n circ ulati n g t u m or D N A (ct D N A). 

E x pl ore a d diti o nal bi o mar kers of A S T X 0 2 9 acti vit y.
4. 0 
S A M P L E SI Z E
T he d ose-escalati o n part of t he st u d y ( P hase 1 Part A) f oll o ws a sta n dar d 3 + 3 st u d y desi g n, wit h a 
c o h ort size of 3 or 6 e val ua ble s u bjects. D ose escalati o n will c o nti n ue u ntil t he M T D f or eac h 
re gi me n e val uate d is deter mi ne d. E val ua ble s u bjects f or d ose-escalati o n decisi o ns i n Part A are 
t h ose w h o ha ve c o m plete d t he first c ycle a n d ha ve recei ve d at least 8 5 % of pla n ne d d oses i n t he 
first c ycle of treat me nt ( or were n ot a ble t o recei ve at least 8 5 % of pla n ne d d oses d ue t o safet y 
c o ncer ns). T he fi nal sa m ple size of part A will de pe n d o n t he assesse d d ose le vels a n d occ urre nce 
of d ose li miti n g t o xicities.


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 6 of 4 6
2 A pril 2 0 2 4
F or Part B ( of P hase 1), a sa m ple size of 1 4 e val ua ble s u bjects will e ns ure a 9 0 % pr o ba bilit y of 
o bser vi n g at least 1 a d verse reacti o n t o treat me nt f or a n y a d verse reacti o n wit h a ≥1 5 %  i nci de nce. 
E val ua ble s u bjects f or Part B are all s u bjects w h o recei ve a n y a m o u nt of st u d y dr u g. 
F or P hase 2, t he sa m ple size is base d o n a Si m o n’s O pti mal 2-sta ge desi g n ( Si m o n 1 9 8 9). Eac h 
c o h ort will e nr oll 1 0 s u bjects i nt o t he first sta ge. S h o ul d ≥2  first-sta ge s u bjects res p o n d, a n 
a d diti o nal 1 9 s u bjects will be e nr olle d i nt o t he sec o n d sta ge. T heref ore, u p t o 2 9 s u bjects will be 
use d f or eac h treat me nt c o h ort. T he sa m ple size, ( 1 0 + 1 9), or 2 9, u n der t his Si m o n’s O pti mal 2-
sta ge desi g n, will ac hie ve a p o wer of 8 0 % t o test t he n ull h y p ot hesis of O R R p 0 ≤0. 1  at a 1-si de d 
al p ha of 0. 0 5 ass u mi n g t he res p o nse rate p 1 is 0. 3. F or Sta ge 2, t he n ull h y p ot hesis will be rejecte d 
if ≥ 6 res p o nses are o bser ve d i n a c o h ort of 2 9 s u bjects. F or C o h ort F ( w hic h will e nr oll patie nts 
wit h vari o us t u m or t y pes a n d ge ne a berrati o ns [ Pr ot oc ol Ta ble 2 ]), t he s p o ns or, wit h a p pr o val of 
t he D S R C, ma y e x pa n d e nr oll me nt t o 1 0 or 2 9 s u bjects f or a partic ular m olec ularl y defi ne d 
s u b p o p ulati o n i n w hic h t he m ost n u m ber of res p o nses are o bser ve d, u n der t he sa me Si m o n’s 
O pti mal 2-sta ge desi g n as f or t he ot her c o h orts f or better assess me nt of acti vit y i n t hat disease 
s u b p o p ulati o n ( O pti o nal C o h ort F e x pa nsi o n). It is e x pecte d t hat n o m ore t ha n 2 s u b p o p ulati o ns 
will be e x pa n de d i n t his ma n ner.
5. 0  
A N A L Y SI S S E T S
5. 1  
All S u bject A nal ysis Set
T he ’ All S u bject A nal ysis Set’ will i ncl u de all scree ne d s u bjects, i ncl u di n g t h ose w h o di d n ot meet 
t he st u d y e ntr y criteria a n d/ or di d n ot recei ve a n y st u d y dr u g. T his data set will o nl y be use d f or 
dis p ositi o n s u m maries. 
5. 2 
E nr olle d S u bject A nal ysis Set
All s u bjects w h o si g n a n i nf or me d c o nse nt f or m (I C F) a n d meet all eli gi bilit y criteria as assesse d 
b y t he i n vesti gat or a n d s p o ns or. I n a d diti o n, eac h s u bject w h o si g ns t he I C F is assi g ne d a u ni q ue 
i de ntificati o n (I D) n u m ber t hat reflects t he st u d y ce nter n u m ber assi g ne d t o t he i n vesti gat or a n d 
t he s u bject at t hat site.
5. 3 
Efficac y A nal ysis Set
T he Efficac y A nal ysis Set will i ncl u de all s u bjects w h o recei ve a n y a m o u nt of st u d y dr u g. Efficac y 
a nal yses will be base d o n t he act ual treat me nt recei ve d o n C ycle 1 Da y 1, w hic h s h o ul d be t he 
assi g ne d c o h ort. T he o verall res p o nse rate ( O R R) a n d D C R a nal ysis will be base d o n s u bjects w h o 
are i n t he Efficac y A nal ysis Set a n d w h o ha d disease assess me nt at baseli ne a n d at least 1 f oll o w- u p 
disease assess me nt or s u bjects w h o die d or st o p pe d treat me nt bef ore t he first sc he d ule d disease 
assess me nt d ue t o cli nical pr o gressi o n or t o xicit y.
5. 4 
Safet y A nal ysis Set


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 7 of 4 6
2 A pril 2 0 2 4
T he Safet y A nal ysis Set will i ncl u de data fr o m all s u bjects w h o recei ve a n y a m o u nt of st u d y dr u g. 
Safet y a nal ysis will be base d o n t he act ual treat me nt recei ve d o n C ycle 1 Da y 1, w hic h s h o ul d be 
t he assi g ne d c o h ort. All data will be i ncl u de d, a n d n o s u bjects e xcl u de d beca use of pr ot oc ol 
vi olati o ns.
5. 5 
P har mac o ki netics A nal ysis Set
T he P K A nal ysis Set will i ncl u de all s u bjects w h o ha ve recei ve d st u d y dr u g wit h a vaila ble plas ma 
c o nce ntrati o ns a n d P K para meters f or A S T X 0 2 9.
5. 6 
P har mac o d y na mic A nal ysis Set
S u bjects will be i ncl u de d i n t he p har mac o d y na mic a n d bi o mar ker a nal yses if t he y ha ve recei ve d 
st u d y dr u g a n d t heir sa m ples were s uccessf ull y c ollecte d a n d a nal yze d.
6. 0 
S C H E D U L E O F A N A L Y S E S
A nal ysis will be c o n d ucte d after all s u bjects ha ve c o m plete d at least o ne R E CI S T assess me nt. T he 
e x pecte d st u d y d urati o n is a p pr o xi matel y 3. 5 years ( 4 2 m o nt hs), i ncl u di n g a p pr o xi matel y 3 6 
m o nt hs f or recr uit me nt a n d a p pr o xi matel y 6 m o nt hs f or safet y f oll o w- u p. T he st u d y starte d i n Q 2 
2 0 1 8.
7. 0 
S T A TI S TI C A L A N A L Y SI S
U nless ot her wise s pecifie d, all statistical tests a n d c o nfi de nce i nter vals ( CIs) descri be d i n t his 
d oc u me nt will be t w o-si de d wit h al p ha 0. 0 5. Data s u m maries a n d listi n gs will be ge nerate d usi n g 
S A S versi o n 9. 4 or a m ore rece nt versi o n ( S A S I nstit ute I nc., Car y, N C, U S A).
T he first d osi n g date is defi ne d as t he first date t he s u bject recei ve d a n y st u d y dr u g. 
A nal ysis ta bles will be s u m marize d b y c o h orts a n d all c o h orts c o m bi ne d f or p hase 1 part A, p hase 
1 part B a n d p hase 2 u nless s pecifie d ot her wise. F or e xa m ple,
• 
P hase 1 A: C o h ort 1, C o h ort 2, …, C o h ort n
• 
P hase 1 B p o w der i n b ottle a n d ta blets
• 
P hase 2: C o h ort A, C o h ort B, …, C o h ort F
• 
P hase 1 A, P hase 1 B, a n d P hase 2
Ta bles ma y be c o m bi ne d a n d/ or se parate d as all o we d b y n u m ber of c o h orts. 
T he A Es will be s u m marize d b y assi g ne d c o h ort at t he o nset of t he A E ( Secti o n 7. 6. 2 ). Efficac y 
a nal yses, la b orat or y tests, vital si g ns, electr ocar di o gra m ( E C G), a n d Easter n C o o perati ve 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 8 of 4 6
2 A pril 2 0 2 4
O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us will be s u m marize d b y assi g ne d c o h ort a n d all 
s u bjects c o m bi ne d ( T otal), u nless ot her wise s pecifie d.
T he f oll o wi n g will be s u m marize d b y assi g ne d c o h ort a n d all s u bjects c o m bi ne d ( T otal), u nless 
ot her wise s pecifie d:

Efficac y a nal yses, 

Treat me nt e mer ge nt a d verse e ve nts ( T E A Es), 

La b orat or y tests, 

Vital si g ns, 

Electr ocar di o gra m ( E C G), a n d 

Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us. 
T he f oll o wi n g data listi n gs b y s u bject i de ntificati o n (I D) n u m ber ( w hic h i ncl u des t he st u d y ce nter 
n u m ber) will be pr o vi de d: 

All e nr olle d s u bjects 

Scree n fail ure s u bjects ( wit h reas o n f or scree n fail ure) 

Dis p ositi o n ( wit h reas o n(s) f or disc o nti n uati o n of treat me nt a n d wit h dra wal fr o m st u d y) 

Pr ot oc ol de viati o ns 

De m o gra p hic a n d baseli ne c haracteristics 

St u d y dr u g a d mi nistrati o n 

I n di vi d ual efficac y data 

S u bjects e xcl u de d fr o m t he efficac y a nal ysis 

T E A Es 

Deat hs (i ncl u di n g pri mar y ca use of deat h) 

Seri o us a d verse e ve nts ( S A Es)

Ot her si g nifica nt T E A Es (i ncl u di n g treat me nt disc o nti n uati o n d ue t o A Es)

C o nc o mita nt me dicati o ns


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 5 9 of 4 6
2 A pril 2 0 2 4

Selecte d la b orat or y meas ure me nts 
A d diti o nal data listi n gs ma y be ge nerate d t o s u p p ort ot her rele va nt disc ussi o ns i n t he cli nical st u d y 
re p ort.
Ge nerall y, all ta bles/fi g ures prese nte d will be s u p p orte d b y a listi n g of t he data s u m marize d i n 
ta ble/fi g ure.
Tai h o/ Bi ostatistics a n d Data 
Ma na ge me nt ( B D M) a n d Cli nical Data I nterc ha n ge Sta n dar ds 
C o ns orti u m ( C DI S C) sta n dar ds will be f oll o we d.  
7. 1 
S u bject Dis p ositi o n 
S u bject dis p ositi o n i ncl u di n g n u m ber of s u bjects e nr olle d, treate d, a n d disc o nti n ue d fr o m st u d y 
dr u g b y reas o n, as well as reas o ns f or wit h dra wal fr o m st u d y (ie, deat h, c o m plete c o nse nt 
wit h dra wal, or l ost t o f oll o w- u p) a n d s u bjects o n g oi n g at data-c ut will be s u m marize d usi n g 
fre q ue ncies a n d perce nta ges base d o n i nf or mati o n c ollecte d o n t he st u d y electr o nic case re p ort 
f or m (e C R F). S u bjects i n t he All- S u bject A nal ysis Set ( Secti o n Err or! Refere nce s o urce n ot 
f o u n d.) will be i ncl u de d i n t he dis p ositi o n a nal ysis.
7. 2  
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
S u bject de m o gra p hic a n d baseli ne c haracteristics will be s u m marize d b y mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m, a n d ma xi m u m f or c o nti n u o us varia bles; a n d b y c o u nts a n d 
perce nta ges f or cate g orical varia bles. F or t he Safet y A nal ysis Set (secti o n 5. 4), all s u bjects w h o 
recei ve d a n y a m o u nt of st u d y dr u g will be i ncl u de d i n t he a nal ysis of de m o gra p hic a n d baseli ne 
c haracteristics. 
S u m maries will be pr o vi de d se paratel y f or eac h re gi me n i n P hase 1 Part A, f or t he R D E c o h ort(s) 
i n P hase 1 Part B, a n d f or eac h c o h ort i n P hase 2. 
T he de m o gra p hic varia bles i ncl u de a ge, a ge cate g or y (( < 1 8, 1 8 < 6 5, 6 5 < 7 5, ≥7 5  years), se x, 
et h nicit y, a n d race. Baseli ne c haracteristics ma y i ncl u de hei g ht, wei g ht, E C O G perf or ma nce 
stat us, pri or a nti-ca ncer t hera p y, a n d best res p o nses t o pri or t hera p y. 
Baseli ne is defi ne d as t he last val ue(s) a vaila ble bef ore or o n t he 1st d osi n g date u nless ot her wise 
s pecifie d. 
7. 3 
P h ar m ac o ki netics A n al yses 
T he P K A nal ysis Set ( Secti o n 5. 5) will be use d f or P K a nal yses.
T he P K para meters will be deri ve d f or eac h s u bject usi n g a n o n-c o m part me ntal a p pr oac h. T he 
f o o d effect o n A S T X 0 2 9 P K para meters will als o be e val uate d. Descri pti ve statistics i ncl u di n g 
mea n, sta n dar d de viati o n, me dia n, a n d ra n ge f or P K para meters f or A S T X 0 2 9 will be s u m marize d. 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 0 of 4 6
2 A pril 2 0 2 4
Detaile d a n d a d diti o nal P K a nal yses are descri be d i n a se parate P K a nal ysis pla n. 
7. 4 
P h ar m ac o d y n a mic A n al yses
Assess me nt of tar get e n ga ge me nt a n d bi o mar ker a nal yses will be perf or me d i n bl o o d a n d t u m or 
tiss ue bi o psies. Sec o n dar y e n d p oi nt bi o mar ker i n vesti gati o n ma y i ncl u de t he f oll o wi n g:
• De m o nstrati o n of tar get e n ga ge me nt i n fres h t u m or tiss ue bi o psies ( w he n a vaila ble) (e g, p R S K 
a n d p E R K i n hi biti o n f oll o wi n g A S T X 0 2 9 treat me nt). 
T his a nal ysis of para meters/ bi o mar kers ma y i ncl u de descri pti ve s u m maries s uc h as mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m, a n d ma xi m u m f or c o nti n u o us varia bles a n d c o u nts a n d perce nta ges 
f or cate g orical varia bles.
T his p har mac o d y na mic data will be ca pt ure d as St u d y Data Ta b ulati o n M o del ( S D T M) data, a n d 
listi n gs pr o vi de d of a n y a nal ysis t hat is d o ne.
E x pl orat or y bi o mar ker i n vesti gati o ns will i ncl u de t he f oll o wi n g:
• E val uati o n of ca ncer cell pr oliferati o n a n d i n d ucti o n of a p o pt osis i n fres h t u m or tiss ue bi o psies 
( w he n a vaila ble).
• S u p pressi o n of m uta nt cl o nes i n ct D N A.
• I de ntificati o n of p ote ntial bi o mar kers of A S T X 0 2 9 acti vit y ( D N A, R N A, or pr otei n) i n bl o o d 
a n d t u m or tiss ue bi o psies (arc hi val a n d fres h bi o psies, w he n a vaila ble).
T he e x pl orat or y p har mac o d y na mic data will n ot be a nal yse d, liste d, or ca pt ure d as St u d y Data 
Ta b ulati o n M o del ( S D T M) data.
7. 5 
Effic ac y V ari a bles a n d A n al yses
Efficac y a nal yses will be base d o n t he Efficac y A nal ysis Set ( Secti o n 5. 3). Efficac y varia bles will 
be s u m marize d usi n g descri pti ve statistics. N o c o m paris o n bet wee n treat me nt se q ue nces will be 
perf or me d. 
A nti-t u m or res p o nse is base d o n Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) v 1. 1 
(Eise n ha uer et al 2 0 0 9 ). T he details of R E CI S T v 1. 1 e val uati o n of res p o nses ca n be f o u n d i n 
pr ot oc ol A p pe n di x 3. T he pri nci pal i n vesti gat or assess me nt of R E CI S T v 1. 1 res p o nse will be 
a nal yze d.
Ta ble 1  pr o vi des a s u m mar y of t he o verall res p o nse stat us calc ulati o n at eac h ti me p oi nt f or 
s u bjects w h o ha ve meas ura ble disease at baseli ne. Details of c o m plete res p o nse ( C R), partial 
res p o nse ( P R), pr o gressi ve disease ( P D), a n d sta ble disease ( S D) assess me nts f or Tar get a n d 
N o ntar get Lesi o ns are pr o vi de d i n A p pe n di x 3 of t he pr ot oc ol. 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 1 of 4 6
2 A pril 2 0 2 4
T a ble 1: 
S u m m ar y of O ver all Assess me nt of Res p o nse
Ti me P oi nt Res p o nse: S u bjects wit h T ar get ( ± N o nt ar get) Dise ase 
T ar get Lesi o ns 
N o nt ar get Lesi o ns 
Ne w Lesi o ns 
O ver all 
Assess me nt of 
Res p o nse 
C R 
C R 
N o 
C R 
C R 
N o n- C R/ N o n- P D 
N o 
P R 
C R 
N ot e val uate d 
N o 
P R 
P R 
N o n- P D or n ot all e val uate d 
N o 
P R 
S D 
N o n- P D or n ot all e val uate d 
N o 
S D 
N ot all e val uate d 
N o n- P D 
N o 
N E 
P D 
A n y 
Yes or N o 
P D 
A n y 
P D 
Yes or N o 
P D 
A n y 
A n y 
Yes  
P D 
C R =c o m plete res p o nse, N E =i ne val ua ble, P D = pr o gressi ve disease, P R = partial res p o nse; S D =sta ble disease.
7. 5. 1
O verall Res p o nse a n d Disease C o ntr ol Rate
T he O R R will be calc ulate d as t he n u m ber of e val ua ble s u bjects w h ose best res p o nse is C R or P R, 
di vi de d b y t he t otal n u m ber of s u bjects e val ua ble f or O R R a nal ysis ( Secti o n 5. 3). T he D C R will 
be calc ulate d as t he n u m ber of s u bjects w h ose best res p o nse is C R, P R, or S D, di vi de d b y t he t otal 
n u m ber of s u bjects e val ua ble f or D C R a nal ysis ( Secti o n 5. 3). T he 9 0 % Cl o p per- Pears o n CIs f or 
t he O R R a n d D C R will be pr o vi de d. 
Best res p o nse f or a s u bject is defi ne d as t he best o verall res p o nse fr o m all p ost baseli ne 
assess me nts of a s u bject i n t he st u d y. W he n S D is belie ve d t o be t he best res p o nse, it m ust als o 
meet t he pr ot oc ol-s pecifie d mi ni m u m ti me fr o m baseli ne ( 6 wee ks). If t he mi ni m u m ti me is n ot 
met w he n S D is ot her wise t he best ti me p oi nt res p o nse, t he s u bject’s best res p o nse de pe n ds o n t he 
s u bse q ue nt assess me nts.
7. 5. 2
D urati o n of Res p o nse
D urati o n of res p o nse will be calc ulate d f or all res p o n ders fr o m t he date of t he first d oc u me ntati o n 
of C R or P R t o t he date of pr o gress or deat h, w hic he ver occ urs first. D urati o n of S D will be 
calc ulate d f or s u bjects w h ose best res p o nse is C R, P R, or S D fr o m t he da y st u d y dr u g was first 
ta ke n t o t he date of disease pr o gressi o n or deat h, w hic he ver occ urs earlier, or t he last disease 
assess me nt f or s u bjects wit h o ut disease pr o gressi o n or deat h. 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 2 of 4 6
2 A pril 2 0 2 4
D urati o n of res p o nse a n d d urati o n of S D will n ot be esti mate d f or s u bjects w h o lea ve t he st u d y 
pri or t o a first assess me nt of res p o nse n or f or s u bjects w h ose best res p o nse is pr o gressi ve disease.
D urati o n of res p o nse a n d d urati o n of S D will be a nal yze d usi n g a K- M met h o d, wit h t he d urati o n 
bei n g ce ns ore d at t he ti me of t he date of st u d y ter mi nati o n f or s u bjects wit h o ut a rela pse or disease 
pr o gressi o n. D urati o n of res p o nse a n d d urati o n of S D will be s u m marize d.   
7. 5. 3
S ur vi val
T he O S is defi ne d as t he n u m ber of da ys fr o m t he da y st u d y dr u g was first ta ke n t o t he date of 
deat h (re gar dless of ca use). S u bjects wit h o ut a d oc u me nte d deat h date will be ce ns ore d o n t he 
last date t he y were k n o w n t o be ali ve. T he O S will be prese nte d usi n g a Ka pla n Meier esti mate. 
T he 9 5 % CI f or me dia n O S will be pr o vi de d usi n g t he Ka pla n- Meier met h o d wit h t he l o g-l o g 
tra nsf or mati o n. All s u bjects i n t he Efficac y A nal ysis Set ( Secti o n 5. 3) will be i ncl u de d i n t he O S 
a nal ysis. T he O S rate at 3, 6, 9 a n d 1 2 m o nt hs (a n d i n s u bse q ue nt 6- m o nt h i ncre me nts if t here 
are partici pa nts still at ris k) will be esti mate d wit h c orres p o n di n g t w o-si de d 9 5 % CIs.
Fre q ue nc y ( n u m ber a n d perce nta ge) of partici pa nts wit h deat h e ve nts a n d ce ns ori n g reas o ns will 
be prese nte d wit h t he o verall e ve nt a n d ce ns or rates. T he e ve nt a n d ce ns ori n g reas o ns are as 
f oll o ws:

Deat h

O n g oi n g a n d n o deat h

Wit h dra wal of c o nse nt

L ost t o f oll o w- u p. 
T he O S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a listi n g
T he P F S is defi ne d as t he n u m ber of da ys fr o m t he start of t he st u d y dr u g t o disease pr o gressi o n 
or deat h, w hic he ver occ urs first. T he P F S will be a nal yze d usi n g a Ka pla n- Meier met h o d, wit h 
P F S ti me bei n g ce ns ore d o n t he date of t he last disease assess me nt. T he 9 5 % CI f or me dia n P F S 
will be pr o vi de d usi n g t he Ka pla n- Meier met h o d wit h t he l o g-l o g tra nsf or mati o n. All s u bjects i n 
t he Efficac y A nal ysis Set ( Secti o n 5. 3) will be i ncl u de d i n t he P F S a nal ysis.
Pr o gressi o n of disease ( P D) is i ncl u de d as a n o verall res p o nse i n Ta ble 1 a b o ve, a n d c o m bi nes 
e val uati o n tar get, n o n-tar get, a n d ne w lesi o ns. Tar get lesi o n res p o nse of P D is at least a 2 0 % 
i ncrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as refere nce t he s mallest s u m o n st u d y 
(t his i ncl u des t he baseli ne s u m if t hat is t he s mallest o n st u d y). N o n-tar get lesi o n res p o nse of P D 
is u ne q ui v ocal pr o gressi o n of e xisti n g n o ntar get lesi o ns. T he a p peara nce of 1 or m ore ne w lesi o ns 
is als o c o nsi dere d pr o gressi o n of disease. A d diti o nal details ca n be f o u n d i n A p pe n di x 3 of t he 
pr ot oc ol, w hic h is base d o n R E CI S T v 1. 1 ( Eise n ha uer et al 2 0 0 9).


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 3 of 4 6
2 A pril 2 0 2 4
7. 6 
S afet y V ari a bles a n d A n al yses
Safet y A nal ysis will be perf or me d usi n g t he Safet y A nal ysis Set ( Secti o n Err or! Refere nce 
s o urce n ot f o u n d.). Safet y is assesse d b y s u bject-re p orte d a n d i n vesti gat or- o bser ve d A Es, al o n g 
wit h p h ysical e xa mi nati o ns, cli nical la b orat or y tests ( he mat ol o g y, c oa g ulati o n, c he mistries, a n d 
uri nal ysis), vital si g ns, c o nc o mita nt me dicati o ns, E C O G perf or ma nce stat us, a n d E C Gs. E x p os ure 
t o st u d y dr u g, T E A Es, deat hs, a n d ca uses of deat hs will be ta b ulate d. 
7. 6. 1 
St u d y Tre at me nt a n d E x p os ure 
St u d y dr u g a d mi nistrati o n will be s u m marize d b y n u m bers of treat me nt c ycles recei ve d, dela ye d 
a n d d ose-re d uce d c ycles, as well as d urati o n of e x p os ure (i n m o nt hs). T hese meas ures of e x p os ure 
will be base d o n d ose a d mi nistrati o ns, d ose re d ucti o ns, d ose i nterr u pti o ns a n d d ose dela ys 
i de ntifie d b y t he i n vesti gat or a n d c ollecte d o n t he st u d y dr u g a d mi nistrati o n e C R Fs. D urati o n of 
e x p os ure, i n m o nt hs, is defi ne d as t he last treat me nt date mi n us t he first date of treat me nt + 1 
di vi de d b y 3 0. 4 3 7 5.
S u m maries of dela ye d, d ose i nterr u pte d, a n d d ose re d uce d c ycles will be pr o vi de d at b ot h s u bject 
a n d c ycle le vels.
D ose i nte nsit y, prese nte d as t he i nci de nce of s u bjects recei vi n g < 8 0 % of t heir i nte n de d d ose, will 
be s u m marize d b y c ycle. D ose i nte nsit y will be calc ulate d as t he act ual t otal d ose di vi de d b y 
pla n ne d t otal d ose f or eac h treat me nt c ycle. 
B ot h c o m plete d or partiall y c o m plete d d ose c ycles are c o u nte d i n t hese s u m maries. 
7. 6. 2  
A d verse E ve nts 
A d verse e ve nts re p orte d b y st u d y s u bjects or o bser ve d b y i n vesti gat ors will be ma p pe d t o t he 
a p pr o priate S yste m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T) acc or di n g t o t he 
Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). Se verit y of A Es will be gra de d usi n g C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) versi o n 4. 0 3 ( pr ot oc ol A p pe n di x 2 ). 
T E A Es are defi ne d as e ve nts t hat first occ urre d or w orse ne d o n or after t he date of t he first d ose 
of st u d y treat me nt u ntil 3 0 da ys after t he last d ose of st u d y treat me nt or u ntil t he start of a p ost-
treat me nt alter nati ve a nti-ca ncer treat me nt, w hic he ver occ urs first, wit h t he f oll o wi n g e xce pti o ns: 
e ve nts t hat occ urre d after 3 0 da ys be y o n d t he last d ose of st u d y treat me nt or t he start of a p ost-
treat me nt alter nati ve a nti-ca ncer treat me nt will als o be c o nsi dere d treat me nt-e mer ge nt if t he e ve nts 
are b ot h seri o us a n d relate d t o t he st u d y treat me nt. F or t he p ur p ose of deter mi ni n g w het her a n A E 
is a T E A E, i nc o m plete A E start a n d st o p dates will be i m p ute d c o nser vati vel y f oll o wi n g t he data 
pr o gra m mi n g c o n ve nti o ns as detaile d i n t he Tai h o Data Pr o gra m mi n g Sta n dar ds.


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 4 of 4 6
2 A pril 2 0 2 4
All A E data c ollecte d i n t he st u d y data base wit h a n A E start date o n or bef ore t he data c ut off date 
will be i ncl u de d i n t he data listi n gs, i ncl u di n g t h ose t hat are n ot treat me nt e mer ge nt. O nl y T E A Es 
will be i ncl u de d i n t he A E s u m mar y ta bles.
A n o verall safet y s u m mar y ta ble c o ntai ni n g c o u nts a n d perce nta ges of s u bjects wit h a n y A E, a n y 
A E Gra de ≥3,  A E lea di n g t o treat me nt disc o nti n uati o n, a n y S A E, a n d s u bcate g ories of S A Es (fatal 
S A Es) will be pr o d uce d.
Relate d e ve nts are t h ose t hat t he I n vesti gat or c o nsi dere d t o be relate d t o st u d y treat me nt as 
descri be d i n t he st u d y pr ot oc ol. All s u m maries of A Es will be s u m marize d b y c o h orts a n d all 
c o h orts c o m bi ne d wit hi n re gi me n wit hi n parts ( A & B), a n d wit hi n P hase (I &II).  Ta bles ma y be 
c o m bi ne d w he n s pace all o ws. 
F or e xa m ple,
• 
P hase 1 A: C o h ort 1, C o h ort 2, …, C o h ort n
• 
P hase 1 B p o w der i n b ottle a n d ta blets
• 
P hase 2: C o h ort A, C o h ort B, …, C o h ort F
• 
P hase 1 A, P hase 1 B, a n d P hase 2
T he n u m ber a n d perce nta ge of s u bjects e x perie nci n g A Es will be s u m marize d b y Me d D R A S O Cs 
(s orte d al p ha beticall y) wit h P Ts s orte d al p ha beticall y wit hi n eac h S O C. T he n u m ber a n d 
perce nta ge of s u bjects e x perie nci n g A Es will als o be s u m marize d b y P T a n d s orte d b y e ve nt 
fre q ue nc y of t he T otal c ol u m n. Relate d A Es, S A Es, a n d relate d S A Es will be s u m marize d 
si milarl y. A s u m mar y of A Es wit h fatal o utc o mes, A Es res ulti n g i n per ma ne nt treat me nt 
disc o nti n uati o n, a n d A Es res ulti n g i n treat me nt dela y, i nterr u pti o n or d ose re d ucti o n will als o be 
pr o vi de d. A d diti o nal s u m maries will be ge nerate d b y S O C, P T a n d C T C A E gra de. F or t hese 
s u m maries, if t he occ urre nce of a partic ular A E f or a gi ve n s u bject is re p orte d m ore t ha n o nce, t he 
e ve nt is o nl y c o u nte d o nce wit h its w orst C T C A E gra de.
7. 6. 3  
D ose Li miti n g T o xicities
D L Ts are A Es t hat occ ur d uri n g t he first c ycle of treat me nt a n d meet 1 or m ore of t he criteria 
o utli ne d i n Secti o n 7. 4 of t he pr ot oc ol. T he A Es meeti n g 1 or m ore of t he criteria are i n dicate d o n 
t he A E e C R F. T he n u m ber a n d perce nta ge of s u bjects w h o ha ve D L Ts will be s u m marize d b y 
c o h ort a n d treat me nt ar m i n P hase 1. 
7. 6. 4  
All-c a use M ort alit y
T he perce nta ge of 3 0- a n d 6 0- da y all-ca use m ortalit y will be calc ulate d base d o n eac h s u bject's 
date of deat h relati ve t o C 1 D 1 (ie, date of deat h mi n us date of C 1 D 1).


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 5 of 4 6
2 A pril 2 0 2 4
7. 6. 5  
C o nc o mit a nt Me dic ati o ns
C o nc o mita nt me dicati o ns are me dicati o ns ta ke n wit h a start date o n or after t he date of t he first 
d ose of st u d y dr u g or t h ose wit h a start date bef ore t he start of t he a d mi nistrati o n of st u d y dr u g a n d 
a st o p date o n or after t he start of t he a d mi nistrati o n of st u d y dr u g. Me dicati o ns ta ke n be y o n d 3 0 
da ys fr o m t he last d ose of st u d y dr u g or after t he start of a p ost-treat me nt alter nati ve a nti-ca ncer 
treat me nt are n ot c o nsi dere d c o nc o mita nt me dicati o ns, u nless t he y are use d f or treati n g a relate d 
S A E. F or t he p ur p ose of i ncl usi o n i n t he c o nc o mita nt me dicati o n ta bles, i nc o m plete me dicati o n 
start a n d st o p dates will be i m p ute d c o nser vati vel y f oll o wi n g t he data pr o gra m mi n g c o n ve nti o ns 
as detaile d i n t he Tai h o Data Pr o gra m mi n g Sta n dar ds. 
C o nc o mita nt me dicati o n will be c o de d b y t he latest versi o n of t he W orl d Healt h Or ga nizati o n 
( W H O) Dr u g Dicti o nar y bef ore t he data d o w nl oa d a n d s u m marize d b y A nat o mical T hera pe utic 
C he mical ( A T C) le vel 2 a n d dr u g na me, s orte d al p ha beticall y, usi n g c o u nts a n d perce nta ges.
7. 6. 6 
L a b or at or y Tests 
S hift ta bles will dis pla y ( 1) s hift fr o m baseli ne gra de t o t he w orst gra de d uri n g t he st u d y, a n d 
( 2) s hift fr o m baseli ne gra de t o t he last gra de at t he e n d of st u d y.
La b orat or y val ues rec or de d as a n i nter val s uc h as " ≥x", " < x", or " 2 +" will be ha n dle d, if necessar y 
f or calc ulati o n p ur p oses, f oll o wi n g t he data pr o gra m mi n g sta n dar ds as detaile d i n t he A Da M data 
re vie wer g ui de.
7. 6. 7  
Vit al Si g ns
Vital si g ns will be s u m marize d b y visit a n d treat me nt gr o u p usi n g pr o p orti o n of s u bjects wit h eac h 
vital si g n bei n g t o o hi g h or t o o l o w acc or di n g t o c o n ve nti o nall y acce pte d vital si g n n or mal ra n ges 
as f oll o ws: 

P ulse rate 1 1 0 b p m or greater.

P ulse rate 5 0 b p m or less.

Diast olic bl o o d press ure 1 1 0 m m H g or greater.

Diast olic bl o o d press ure 5 5 m m H g or less.

S yst olic bl o o d press ure 1 8 0 m m H g or greater.

S yst olic bl o o d press ure 8 0 m m H g or less.

Res pirati o n rate 2 0 breat hs/ mi n or greater.

B o d y te m perat ure 3 9° C or greater.


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 6 of 4 6
2 A pril 2 0 2 4
7. 6. 8 
Electr oc ar di o gr a m ( E C G)
T he 1 2-lea d E C Gs will be perf or me d at scree ni n g a n d pre d ose a n d 2 h o urs ( ± 3 0 mi n utes) p ost d ose 
o n C 1 D 1 a n d C 2 D 1; t he y will be perf or me d pre d ose at all ot her ti me p oi nts o n t he d osi n g da ys 
a n d at t he Treat me nt Ter mi nati o n visit as i n dicate d. F or eac h E C G para meter ( heart rate, R R 
i nter val, P R i nter val, Q R S d urati o n, Q T i nter val, a n d Q T c orrecte d f or heart rate usi n g Fri dericia’s 
f or m ula ( Q Tc F)), t he mea n of t he a vaila ble tri plicate E C G val ues will be calc ulate d. 
E C G fi n di n gs will be liste d b y s u bject a n d, if data per mit, ma y be s u m marize d as f oll o ws:
• 
T he val ues a n d res pecti ve c ha n ges fr o m baseli ne ma y be s u m marize d b y visit. .
• 
S u m maries ma y als o be pr o vi de d of t he ma xi m u m p ost- baseli ne a bs ol ute Q Tc F a n d t he 
ma xi m u m p ost- baseli ne i ncrease i n Q Tc F. 
7. 6. 9 
E C O G Perf or m a nce St at us
S hift ta bles f or E C O G fr o m baseli ne t o t he w orst gra de, a n d fr o m t he baseli ne t o t he last a vaila ble 
gra de will be pr o vi de d.
7. 6. 1 0 
Ec h oc ar di o gr a m / M ulti g ate d Ac q uisiti o n ( E C H O/ M U G A)
Data will be preser ve d i n a St u d y Data Ta b ulati o n M o del ( S D T M) dataset. N o partic ular a nal ysis 
will be c o n d ucte d.
7. 6. 1 1 
P h ysic al E x a mi n ati o n
P h ysical e xa mi nati o n data will be preser ve d i n a S D T M dataset. N o partic ular a nal ysis will be 
c o n d ucte d.
7. 7  
H a n dli n g of Missi n g D at a a n d Ot her D at a A n o m alies
N o missi n g data i m p utati o ns are pla n ne d f or t he st u d y, e xce pt f or selecti n g treat me nt e mer ge nt 
A Es as s pecifie d i n Secti o n 7. 6. 2 , a n d f or i ncl usi o n i n c o nc o mita nt me dicati o n a nal ysis as s pecifie d 
i n Secti o n 7. 6. 5 . S u bjects l ost t o f oll o w- u p will be i ncl u de d i n statistical a nal yses t o t he p oi nt of 
t he data c ut- off date.
7. 8  
H a n dli n g of Pr ot oc ol De vi ati o ns
Pr ot oc ol de viati o ns  will be ta b ulate d b y cate g or y ( maj or/ mi n or) a n d liste d b y s u bject.    
Maj or de viati o ns are t h ose t hat mi g ht si g nifica ntl y affect c o m plete ness acc urac y a n d or rea da bilit y 
of st u d y data or t hat ma y si g nifica ntl y affect a s u bject ri g ht, safet y or well bei n g. Mi n or de viati o ns 
are a n y c ha n ges/alterati o ns t hat ha ve n ot or d o n ot ha ve t he p ote ntial t o: 1) a d versel y affect t he 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 7 of 4 6
2 A pril 2 0 2 4
ri g hts, welfare, or safet y of t he s u bjects, 2) a d versel y affect t he i nte grit y of t he researc h data, or 3) 
affect t he s u bject’s willi n g ness t o partici pate i n t he st u d y.
7. 9  
C h a n ges fr o m Pr ot oc ol
‘ O verall Res p o nse’ i n Ta ble 1 3  of t he pr ot oc ol (a me n d me nt 5) has bee n c ha n ge d t o ‘ O verall 
Assess me nt of Res p o nse’ i n Ta ble 1 of t his S A P.
T he pr ot oc ol pla n ne d f or p ossi ble Re gi me n 1 (c o nti n u o us), Re gi me n 2 (i nter mitte nt), a n d o pti o nal 
Re gi me n 3 (i nter mitte nt). H o we ver, o nl y Re gi me n 1 (c o nti n u o us) was o pe ne d t o e nr oll me nt. T he 
a nal yses i n Secti o n Err or! Refere nce s o urce n ot f o u n d.  will descri be t he a nal ysis t o be c o n d ucte d 
usi n g t he data a vaila ble at c o m pleti o n of P hase 1.
I n secti o n 5. 2 , t he E nr olle d S u bject A nal ysis Set has bee n a d de d.
8. 0 
S U P P O R TI N G D O C U M E N T A TI O N
8. 1  
A p pe n di x 1: A bs ol ute Ne utr o p hil C o u nt ( A N C) Deri v ati o n 
W he n a he mat ol o g y differe ntial is c o m plete d, t he a bs ol ute ne utr o p hil c o u nt ( A N C) will be 
deri ve d as f oll o ws:

If t he differe ntial is re p orte d i n a bs ol ute val ues, A N C is e q ual t o t he re p orte d 
“ Ne utr o p hils (a bs ol ute)” val ue wit h t he ass ociate d u nits f or t hat val ue.

If t he differe ntial is re p orte d i n perce nta ges, a n d t he se g me nte d ne utr o p hils a n d ba n d 
ne utr o p hils are N O T re p orte d se paratel y, A N C is e q ual t o t he re p orte d “ Ne utr o p hils %” 
val ue m ulti plie d b y t he W B C val ue a n d di vi de d b y 1 0 0. T he c orres p o n di n g u nits will be 
t he sa me as t he W B C u nits.
If t he differe ntial is re p orte d i n perce nta ges, a n d t he se g me nte d ne utr o p hils a n d ba n d ne utr o p hils 
A R E re p orte d se paratel y, A N C is e q ual t o t he s u m of t he re p orte d “ Se g me nte d Ne utr o p hils %”  
a n d “ Ba n d Ne utr o p hils %”, m ulti plie d b y t he W B C val ue a n d di vi de d b y 1 0 0. T he c orres p o n di n g 
u nits will be t he sa me as t he W B C u nits.
8. 2  
A p pe n di x 3: S u m m ar y of C h a n ges
R ati o n ale f or Versi o n x. x
S u m m ar y of C h a n ges: N A


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 8 of 4 6
2 A pril 2 0 2 4
9. 0  
R E F E R E N C E S
C ha p ma n P B, Ha usc hil d A, R o bert C, Haa ne n J B, Asciert o P, Lar ki n J, et al. I m pr o ve d s ur vi val 
wit h ve m urafe ni b i n mela n o ma wit h B R A F V 6 0 0 E m utati o n. N E n gl J Me d. 
2 0 1 1; 3 6 4( 2 6): 2 5 0 7 −2 5 1 6. 
Eise n ha uer E A, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R, et al. Ne w res p o nse 
e val uati o n criteria i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 
2 0 0 9; 4 5( 2): 2 2 8 – 2 4 7.
E mer y C M, Vija ye n dra n K G, Zi pser M C, Sa w yer A M, Ni u L, Ki m JJ, et al. M E K 1 m utati o ns 
c o nfer resista nce t o 
M E K 
a n d 
B- R A F i n hi biti o n. 
Pr oc 
Natl 
Aca d 
Sci 
U 
S 
A. 
2 0 0 9; 1 0 6( 4 8): 2 0 4 1 1 −2 0 4 1 6. 
Far k o na S, Dia ma n dis E P, Blas uti g I M. Ca ncer i m m u n ot hera p y: t he be gi n ni n g of t he e n d of 
ca ncer? B M C Me d. 2 0 1 6; 1 4: 7 3. 
Fla hert y K T, I nfa nte J R, Da u d A, G o nzalez R, Keff or d R F, S os ma n J, et al. C o m bi ne d B R A F a n d 
M E K i n hi biti o n 
i n 
mela n o ma 
wit h 
B R A F 
V 6 0 0 
m utati o ns. 
N 
E n gl 
J 
Me d. 
2 0 1 2; 3 6 7( 1 8): 1 6 9 4 −7 0 3. 
Frie d ma n A A, Letai A, Fis her D E, Fla hert y K T. Precisi o n me dici ne f or ca ncer wit h ne xt-
ge nerati o n f u ncti o nal dia g n ostics. Nat Re v Ca ncer. 2 0 1 5; 1 5: 7 4 7 −7 5 6. 
Ha usc hil d A, Gr o b JJ, De mi d o v L V, J o uar y T, G utz mer R, Mill war d M, et al. Da brafe ni b i n 
B R A F- m utate d metastatic mela n o ma: a m ultice ntre, o pe n-la bel, p hase 3 ra n d o mise d c o ntr olle d 
trial. La ncet. 2 0 1 2; 3 8 0( 9 8 3 9): 3 5 8 −3 6 5. 
I nfa nte J R, Ja n k u F, T olc her A W, Patel M R, S ulli va n RJ, Fla hert y K. D ose escalati o n sta ge of a 
first-i n-class p hase I st u d y of t he n o vel oral E R K 1/ 2 ki nase i n hi bit or B V D- 5 2 3 ( uli xerti ni b) i n 
patie nts wit h a d va nce d s oli d t u m ors [ A S C O a bstract]. J Cli n O nc ol. 2 0 1 5; 3 3: 1 5 (s u p pl): 2 5 0 6. 
I nfa nte J R, Ja n k u F, T olc her A W, Patel M R, S ulli va n RJ, Fla hert y K. D ose escalati o n sta ge of a 
first-i n-class p hase I st u d y of t he n o vel oral E R K 1/ 2 ki nase i n hi bit or B V D- 5 2 3 ( uli xerti ni b) i n 
patie nts wit h a d va nce d s oli d t u m ors. Pa per prese nte d at: 2 0 1 5 A S C O A n n ual Meeti n g; 2 9 Ma y t o 
0 6 J u n 2 0 1 5; C hica g o, Illi n ois. htt ps:// meeti n gli brar y.asc o. or g/rec or d/ 1 1 1 9 0 1/sli de. Accesse d 2 0 
N o ve m ber 2 0 1 7. 
Li B T, Ja n k u F, Patel M R, S ulli va n RJ, Fla hert y K, B uc h bi n der EI, et al. First-i n-class oral E R K 1/ 2 
i n hi bit or Uli xerti ni b ( B V D- 5 2 3) i n patie nts wit h a d va nce d s oli d t u m ors: fi nal res ults of a p hase I 
d ose escalati o n a n d e x pa nsi o n st u d y. Pa per prese nte d at: 2 0 1 7 A S C O A n n ual Meeti n g; 0 2 t o 0 6 
J u ne 2 0 1 7; C hica g o, Illi n ois. htt ps:// meeti n gli brar y.asc o. or g/rec or d/ 1 4 4 5 7 7/a bstract. Accesse d 2 0 
N o ve m ber 2 0 1 7. 


T ai h o O nc ol o g y, I nc.
A S T X 0 2 9
St atistic al A n al ysis Pl a n – A S T X 0 2 9- 0 1 (f or A d v a nce d S oli d T u m ors)
C o nfi de nti al I nf or m ati o n
P a ge 6 9 of 4 6
2 A pril 2 0 2 4
Little A S, Bal ma n n o K, Sale 
MJ, S mit h P D, C o o k SJ. T u m o ur cell res p o nses t o 
M E K 1/ 2 
i n hi bit ors: ac q uire d resista nce a n d pat h wa y re m o delli n g. Bi oc he m S oc Tra ns. 2 0 1 2; 4 0( 1): 7 3 −7 8. 
Nazaria n R, S hi H, Wa n g Q, K o n g X, K o ya R C, Lee H, et al. Mela n o mas ac q uire resista nce t o B-
R A F( V 6 0 0 E) i n hi biti o n b y R T K or N- R A S u pre g ulati o n. Nat ure. 2 0 1 0; 4 6 8( 7 3 2 6): 9 7 3 – 9 7 7. 
Nissa n M H, R ose n N, S olit D B. E R K pat h wa y i n hi bit ors: H o w l o w s h o ul d we g o? Ca ncer Disc o v. 
2 0 1 3; 3: 7 1 9 – 7 2 1.  
S olit 
D B, 
R ose n 
N. 
Resista nce t o 
B R A F i n hi biti o n i n 
mela n o mas. 
N 
E n gl J 
Me d. 
2 0 1 1; 3 6 4( 8): 7 7 2 −7 7 4. 
S ulli va n RJ, I nfa nte J R, Ja n k u F, W o n g DJ L, S os ma n J A, Kee d y V, et al. First-i n- Class E R K 1/ 2 
i n hi bit or uli xerti ni b ( B V D- 5 2 3) i n patie nts wit h M A P K m uta nt a d va nce d s oli d t u m ors: res ults of 
a P hase I D ose-escalati o n a n d e x pa nsi o n st u d y. Ca ncer Disc o v. 2 0 1 8; 8( 2): 1 8 4- 1 9 5.  
Var ga A, S oria J C, H olle bec q ue A, L o R uss o P, Vais ha m pa ya n U, O k hra, K, et al. A first-i n- h u ma n 
p hase I st u d y t o e val uate t he E R K 1/ 2 i n hi bit or G D C- 0 9 9 4 i n patie nts wit h a d va nce d s oli d t u m ors 
[ E O R T C a bstract]. E ur J Ca ncer. 2 0 1 6; 6 9:(s u p pl 1): S 1 1. 
Var ga A, S oria J C, H olle bec q ue A, L o R uss o P, Vais ha m pa ya n U, O k hra, K, et al. A first-i n- h u ma n 
p hase I st u d y t o e val uate t he E R K 1/ 2 i n hi bit or G D C- 0 9 9 4 i n patie nts wit h a d va nce d s oli d t u m ors. 
Pa per prese nte d at: 2 8 t h E O R T C- N CI- A A C R S y m p osi u m o n 
M olec ular Tar gets a n d Ca ncer 
T hera pe utics;  
2 9  
N o ve m ber  
t o  
0 2  
Dece m ber  
2 0 1 6;  
M u nic h,  
Ger ma n y. 
htt p:// w w w.ecc o or g.e u/ E ve nts/ Past-c o nfere nces/ E N A 2 0 1 6/ We bcasts. 
Accesse d 2 0 
N o ve m ber 
2 0 1 7. 
Wa gle N, E mer y C, Ber ger M F, Da vis MJ, Sa w yer A, P oc ha nar d P, et al. Dissecti n g t hera pe utic 
resista nce t o R A F i n hi biti o n i n 
mela n o ma b y t u m or ge n o mic pr ofili n g. J Cli n 
O nc ol. 
2 0 1 1; 2 9( 2 2): 3 0 8 5 – 3 0 9 6.  


A st e x
T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: A S T X 0 2 9- 0 1 S oli d T u m or s S A P P h a s e s 1 a n d 2 v 1. 0
D o c u m e nt N u m b er: 1 0 0 0 2 9 8 7 7 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Cli ni c al A p pr o v al
0 3- A pr- 2 0 2 4
1 5: 3 5: 3 7
Bi o st ati sti c s A p pr o v al
0 2- A pr- 2 0 2 4
1 7: 2 4: 2 1
Bi o st ati sti c s A p pr o v al
0 2- A pr- 2 0 2 4
1 7: 4 7: 0 8