Study of ASTX029 in Subjects With Advanced Solid Tumors

A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in Subjects With Advanced Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumor, Adult
• Intervention / Treatment: Drug: ASTX029; Drug: ASTX029

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.

• Study Type: Interventional
• Enrollment (Actual): 192
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Marseille, France, 13005
    • Hôpital de la Timone Site #201
  • Rhone-Alpes
    • Lyon, Rhone-Alpes, France, 69373
      • Centre Léon Bérard Service d'Oncologie Médicale Site#202
• Spain
  • Barcelona, Spain, 08916
    • Hospital Universitari Germans Trias i Pujol
  • Barcelona, Spain, 08028
    • Institut Català d'Oncologia Badalona Site#240
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebrón Servicio de Oncología, Sala coordinación UITM Site#243
  • Barcelona, Spain, 8028
    • Hospital Universitario Dexeus Site#241
  • Madrid, Spain, 28027
    • Clinica Universidad de Navarra Madrid Site #242
  • Madrid, Spain, 28027
    • Clínica Universidad de Navarra Site#242
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Foundation Trust
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • The Newcastle Upon Tyne Hospitals NHS Foundation Trust Site #221
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital Site #224
  • England
    • Manchester, England, United Kingdom, M20 4BX
      • The Christie NHS Foundation Trust Site#220
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • University of Southern California Norris Comprehensive Cancer Center Site#114
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute Site# 107
    • Newport Beach, California, United States, 92658
      • Hoag Memorial Hospital Site#115
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center Site #121
    • San Francisco, California, United States, 94115-2378
      • California Pacific Medical Center - Sutter Pacific Medical Center Site#117
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Smilow Cancer Hospital at Yale New Haven Site#105
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Holden Comprehensive Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • The Sidney Kimmel Comprehensive Cancer Center Site#106
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Site#103
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute Site#104
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Rogel Cancer Center Site #113
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center - Herbert Irving Pavilion Site#112
  • Oregon
    • Portland, Oregon, United States, 97223
      • Providence Portland Medical Center Site #118
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University Site #122
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania-Abramson Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center Site#111
    • San Antonio, Texas, United States, 78229
      • START - South Texas Accelerated Research Therapeutics, LLC Site# 101
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists Site#102

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participants 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. Participants 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, participants must also have documented gene alterations in the MAPK pathway as detailed in the protocol.
4. In Phase 1 Part B of the protocol, participants must have disease lesions that are amenable to biopsy.
5. In the Phase 2 portion of the protocol, participants must have measurable disease according to RECIST v1.1.
6. Eastern Cooperative Oncology Group performance status 0 to 2.

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

   1. Aspartate aminotransferase (AST) and alanine aminotransferase ≤2×upper limit of normal (ULN) or ≤3 ULN in the presence of liver metastases.
   2. Total serum bilirubin ≤1.5×ULN.
   3. Absolute neutrophil count (ANC) ≥1500 cells/mm3.
   4. Platelet count ≥100,000 cells/mm3.
   5. Calculated creatinine clearance (by the standard Cockcroft Gault formula) of ≥50 mL/min or glomerular filtration rate of ≥50 mL/min.
8. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [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 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 female partners 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 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:

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 participants safety or the integrity of study outcomes or interfere with the absorption or metabolism of ASTX029.

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

   1. Cytotoxic chemotherapy or radiotherapy within 3 weeks prior. Palliative radiotherapy to a single lesion within 2 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) not stabilized or resolved to ≤Grade 1.
   2. Monoclonal antibodies within 4 weeks prior. Any encountered treatment-related toxicities not stabilized or resolved to ≤Grade 1.
   3. Molecularly targeted drug or investigational drugs, without the potential for delayed toxicity, within 4 weeks of the first dose of study treatment or 5 half-lives (minimum 14 days), whichever is shorter. 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:

   1. Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.
   2. Congestive cardiac failure of ≥Grade 3 severity according to New York Heart Association functional classification defined as patients with marked limitation of activity and who are comfortable only at rest.
   3. Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days).
   4. History or evidence of long QT interval corrected for heart rate (QTc), ventricular arrhythmias including ventricular bigeminy, complete left bundle branch block, clinically significant bradyarrhythmias such as sick sinus syndrome, second- and third-degree atrioventricular (AV) block, presence of cardiac pacemaker or defibrillator, or other significant arrhythmias.
   5. 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.)
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 participant to high risk of noncompliance with the protocol treatment or assessments.

10. History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including:

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

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

19

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1A: Cohort 1 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 2 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 3 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 4 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 5 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 6 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 7 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 8 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 9 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 10 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 11 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1A: Cohort 12 Dose Escalation; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 1B Dose Expansion; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 2: Cohort A; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 2: Cohort B; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 2: Cohort C; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 2: Cohort D; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 2: Cohort E; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet
Experimental: Phase 2: Cohort F; 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.	Drug: ASTX029; PiB; Drug: ASTX029; Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)	DLTs were defined as adverse events (AEs) graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria that occurred during the first cycle of treatment and represented any 1 of the following: grade 4 thrombocytopenia of any duration; ≥grade 3 hematologic toxicity with complications (e.g., 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; ≥grade 2 eye disorders; symptomatic grade 2 cutaneous toxicities (including skin rash); any other ≥grade 3 nonhematologic AE except grade 3 nausea, vomiting, or diarrhea; Any event that, in the opinion of the Data and Safety Review Committee (DSRC), would suggest that further dose escalation would put subjects at unacceptable risk.	Cycle 1 (cycle length = 21 days)
Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAEs are defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a posttreatment alternative anti-cancer treatment, whichever occurs first, with the following exceptions: events that occurred after 30 days beyond the last dose of study treatment or the start of a posttreatment alternative anti-cancer treatment will also be considered treatment-emergent if the events are both serious and related to the study treatment.	From first dose of study drug up to 30 days after last dose (Up to 74 months)
Phase 2: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	The ORR was calculated as the number of evaluable participants whose best response was complete response (CR) or partial response (PR), divided by the total number of participants evaluable for ORR analysis. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Percentages were rounded off to the nearest single decimal place	Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 74 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029	As per planned analysis, data for participants from Part A (Dose Escalation) and Part B (Expansion) were combined for Cohort 11 (200 mg). 2 participants who received 200 and 280 mg respectively, in Cycle 1 Day1 (C1D1), received 120 mg in Cycle 2 and Day 1 (C2D1) and hence counted in Cohort 10. 1 participant who received 280 mg in C1D1, received 200 mg in C2D1 and hence counted in Cohort 11.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029	As per planned analysis, data for participants from Part A (Dose Escalation) and Part B (Expansion) were combined for Cohort 11 (200 mg). 2 participants who received 200 and 280 mg respectively, in C1D1 received 120 mg in C2D1 and hence counted in Cohort 10. 1 participant who received 280 mg in C1D1, received 200 mg in C2D1 and hence counted in Cohort 11.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029	As per planned analysis, data for participants from Part A (Dose Escalation) and Part B (Expansion) were combined for Cohort 11 (200 mg). 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10. 1 participant who received 280 mg in C1D1, received 200 mg in C2D1 and hence counted in Cohort 11.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029	As per planned analysis, data for participants from Part A (Dose Escalation) and Part B (Expansion) were combined for Cohort 11 (200 mg). 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10. 1 participant who received 280 mg in C1D1, received 200 mg in C2D1 and hence counted in Cohort 11.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029	As per planned analysis, data for participants from Part A (Dose Escalation) and Part B (Expansion) were combined for Cohort 11 (200 mg). 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10. 1 participant who received 280 mg in C1D1, received 200 mg in C2D1 and hence counted in Cohort 11. Data for Cmin was calculated and analyzed for C2D1 only.	Pre-dose and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycle 2 (Cycle length = 21 days)
Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029	As per planned analysis, data for participants from Part A (Dose Escalation) and Part B (Expansion) were combined for Cohort 11 (200 mg). 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10. 1 participant who received 280 mg in C1D1, received 200 mg in C2D1 and hence counted in Cohort 11.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Elimination Half-Life (T1/2) of ASTX029	As per planned analysis, data for participants from Part A (Dose Escalation) and Part B (Expansion) were combined for Cohort 11 (200 mg). 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10. 1 participant who received 280 mg in C1D1, received 200 mg in C2D1 and hence counted in Cohort 11.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Effect of Food on AUC0-24 of ASTX029	The food effect was to be analyzed only for tablet dosage forms. The participants who were administered 80 mg and 120 mg tablets, under both fed and fasted conditions were reported. As 200 mg dose was administered, as tablets, only under fasted conditions, hence food effect was not assessed for 200 mg dose. The statistical comparison between fed and fasted state treatment arm groups of 80 mg and 120 mg doses is reported in this outcome measure for food effect. The 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Effect of Food on AUC0-inf of ASTX029	The food effect was to be analyzed only for tablet dosage forms. The participants who were administered 80 mg and 120 mg tablets, under both fed and fasted conditions were reported. As 200 mg dose was administered, as tablets, only under fasted conditions, hence food effect was not assessed for 200 mg dose. The statistical comparison between fed and fasted state treatment arm groups of 80 mg and 120 mg doses is reported in this outcome measure for food effect. The 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Effect of Food on Cmax of ASTX029	The food effect was to be analyzed only for tablet dosage forms. The participants who were administered 80 mg and 120 mg tablets, under both fed and fasted conditions were reported. As 200 mg dose was administered, as tablets, only under fasted conditions, hence food effect was not assessed for 200 mg dose. The statistical comparison between fed and fasted state treatment arm groups of 80 mg and 120 mg doses is reported in this outcome measure for food effect. The 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Effect of Food on Tmax of ASTX029	The food effect was to be analyzed only for tablet dosage forms. The participants who were administered 80 mg and 120 mg tablets, under both fed and fasted conditions were reported. As 200 mg dose was administered, as tablets, only under fasted conditions, hence food effect was not assessed for 200 mg dose. The statistical comparison between fed and fasted state treatment arm groups of 80 mg and 120 mg doses is reported in this outcome measure for food effect. The 2 participants who received 200 and 280 mg respectively, in C1D1, received 120 mg in C2D1 and hence counted in Cohort 10.	Pre-dose on Day 1 of Cycles 1 and 2 and at 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycles 1 and 2 (Cycle length = 21 days)
Phase 1: Inhibition of Phosphorylated Ribosomal S6 Kinase (pRSK) Protein in Response to ASTX029 Treatment in Tumor Biopsies as Assessed by H Score	The protein expression level is quantified through the H-score, calculated from staining intensity within the target cell region. H-Score = (3x % of cells with staining graded 3) + (2x % of cells with staining graded 2) + % of cells with staining graded 1. H-Score ranges between 0 to 300. The H-score is for sum of cytoplasmic H-Score (C pRSK H-Score) and nuclear H-Scores (N pRSK H-Score). C pRSK H-Scores, and nuclear H-Scores were combined to give a single H-score.	4 hours post-dose on Day 8 of Cycle 2 (Cycle length = 21 days)
Phase 1: Progression Free Survival (PFS)	The PFS was defined as the number of months from the start of the study treatment to disease progression or death, whichever occurs first. The PFS was 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 was provided using the Kaplan-Meier procedure.	Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Phase 1: Overall Survival (OS)	The OS was defined as the number of months from the day the participant was randomized to the date of death (regardless of cause). Participants without a documented death date were censored on the last date they were known to be alive. The OS was presented using a Kaplan-Meier estimate. The 90% CI for median OS was provided using the Kaplan-Meier procedure.	Up to 82 months
Phase 1: Disease Control Rate (DCR)	DCR was calculated as the number of participants whose best response was CR, PR, or stable disease (SD), divided by the total number of participants evaluable for DCR analysis. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. PR was defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Percentages were rounded off to the nearest single decimal place.	Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Phase 1: Duration of Response (DoR)	Duration of response was calculated for all responders from the date of the earliest assessment of CR or PR to the date of relapse or death, whichever occurred earlier, or the last disease assessment date for participants without a relapse or death. Duration of SD was calculated for participants 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 occurred earlier, or the last disease assessment for participants without disease progression or death.	Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Phase 2: AUC0-24 of ASTX029		Pre-dose on Day 1 of Cycles 1, and 3; at 0.5,1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycle 1, and at 0.5,1, 2, 4, and 8 hours post-dose on Day 1 of Cycle 3 (Cycle length = 21 days)
Phase 2: AUC0-last of ASTX029		Pre-dose on Day 1 of Cycles 1, and 3; at 0.5,1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycle 1, and at 0.5,1, 2, 4, and 8 hours post-dose on Day 1 of Cycle 3 (Cycle length = 21 days)
Phase 2: AUC0-inf of ASTX029	Data for Auc0-inf was collected and analyzed for C1D1 only.	Pre-dose on Day 1 of Cycle 1; and at 0.5,1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycle 1 (Cycle length = 21 days)
Phase 2: Cmax of ASTX029		Pre-dose on Day 1 of Cycles 1, and 3; at 0.5,1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycle 1, and at 0.5,1, 2, 4, and 8 hours post-dose on Day 1 of Cycle 3 (Cycle length = 21 days)
Phase 2: Cmin of ASTX029	Data for Cmin was calculated and analyzed for C3D1 only.	Pre-dose on Day 1 of Cycle 3; and at 0.5,1, 2, 4, and 8 post-dose on Day 1 of Cycle 3 (Cycle length = 21 days)
Phase 2: Tmax of ASTX029		Pre-dose on Day 1 of Cycles 1, and 3; at 0.5,1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycle 1, and at 0.5,1, 2, 4, and 8 hours post-dose on Day 1 of Cycle 3 (Cycle length = 21 days)
Phase 2: T1/2 of ASTX029	Data for T1/2 was collected and analyzed for C1D1 only.	Pre-dose on Day 1 of Cycle 1; at 0.5,1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycle 1 (Cycle length = 21 days)
Phase 2: Progression Free Survival	The PFS was defined as the number of months from the start of the study treatment to disease progression or death, whichever occurs first. The PFS was 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 was provided using the Kaplan-Meier procedure.	Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Phase 2: Overall Survival	The OS was defined as the number of months from the day the participant was randomized to the date of death (regardless of cause). Participants without a documented death date were censored on the last date they were known to be alive. The OS was presented using a KM estimate. The 90% CI for median OS was provided using the Kaplan-Meier procedure.	Up to 82 months
Phase 2: Disease Control Rate	DCR was calculated as the number of participants whose best response was CR, PR, or SD, divided by the total number of participants evaluable for DCR analysis. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. PR was defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Phase 2: Duration of Response	Duration of response was calculated for all responders from the date of the earliest assessment of CR or PR to the date of relapse or death, whichever occurred earlier, or the last disease assessment date for participants without a relapse or death. Duration of SD was calculated for participants 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 occurred earlier, or the last disease assessment for participants without disease progression or death.	Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)

Collaborators and Investigators

• Sponsor: Taiho Oncology, Inc.

Publications and helpful links

General Publications

• Munck JM, Berdini V, Bevan L, Brothwood JL, Castro J, Courtin A, East C, Ferraldeschi R, Heightman TD, Hindley CJ, Kucia-Tran J, Lyons JF, Martins V, Muench S, Murray CW, Norton D, O'Reilly M, Reader M, Rees DC, Rich SJ, Richardson CJ, Shah AD, Stanczuk L, Thompson NT, Wilsher NE, Woolford AJ, Wallis NG. ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK. Mol Cancer Ther. 2021 Oct;20(10):1757-1768. doi: 10.1158/1535-7163.MCT-20-0909. Epub 2021 Jul 30.

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2018
• Primary Completion (Actual): August 1, 2024
• Study Completion (Actual): March 3, 2025

Study Registration Dates

• First Submitted: April 18, 2018
• First Submitted That Met QC Criteria: May 8, 2018
• First Posted (Actual): May 9, 2018

Study Record Updates

• Last Update Posted (Actual): July 3, 2025
• Last Update Submitted That Met QC Criteria: June 16, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Neoplasms; Antineoplastic Agents; Solid Tumors; ERK; MAPK
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: ASTX029-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No