Solid Tumor, Adult
Conditions
Keywords
Neoplasms, Solid Tumors, Antineoplastic Agents, MAPK, ERK
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.
Interventions
DRUGASTX029
PiB
Sponsors
Taiho Oncology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (cycle length = 21 days) | 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. |
| Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose of study drug up to 30 days after last dose (Up to 74 months) | 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. |
| Phase 2: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 74 months) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | 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) | 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. |
| Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | 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) | 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. |
| Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 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) | 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. |
| Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | 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) | 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. |
| Phase 1: Elimination Half-Life (T1/2) of ASTX029 | 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) | 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. |
| Phase 1: Effect of Food on AUC0-24 of ASTX029 | 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) | 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. |
| Phase 2: Progression Free Survival | Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months) | 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. |
| Phase 1: Effect of Food on AUC0-inf of ASTX029 | 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) | 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. |
| Phase 1: Effect of Food on Cmax of ASTX029 | 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) | 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. |
| Phase 1: Effect of Food on Tmax of ASTX029 | 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) | 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. |
| Phase 1: Inhibition of Phosphorylated Ribosomal S6 Kinase (pRSK) Protein in Response to ASTX029 Treatment in Tumor Biopsies as Assessed by H Score | 4 hours post-dose on Day 8 of Cycle 2 (Cycle length = 21 days) | 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. |
| Phase 1: Progression Free Survival (PFS) | Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months) | 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. |
| Phase 2: T1/2 of ASTX029 | 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) | Data for T1/2 was collected and analyzed for C1D1 only. |
| Phase 1: Disease Control Rate (DCR) | Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months) | 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. |
| Phase 1: Duration of Response (DoR) | Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months) | 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. |
| 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 | 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) | Data for Auc0-inf was collected and analyzed for C1D1 only. |
| 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 | 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) | Data for Cmin was calculated and analyzed for C3D1 only. |
| 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: Overall Survival | Up to 82 months | 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. |
| Phase 2: Disease Control Rate | Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months) | 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. |
| Phase 2: Duration of Response | Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months) | 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. |
| Phase 1: Overall Survival (OS) | Up to 82 months | 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. |
| Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | 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) | 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. |
| Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | 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) | 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. |
Countries
France, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part at regional sites in United States (US), France, Spain, and United Kingdom (UK) from 07 May 2018 to 03 March 2025.
Pre-assignment details
A total of 192 participants were enrolled in the study to receive ASTX029, of which 2 participants died before receiving treatment. The study was conducted in 2 phases: Phase 1 included Cohorts 1-12 in Part A (Dose Escalation) and a single cohort for Part B (Dose Expansion) and Phase 2 included Cohorts A to F.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1A: Cohort 1 Dose Escalation Participants received ASTX029 10 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. | 3 |
| 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. | 3 |
| 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. | 3 |
| 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. | 5 |
| 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. | 10 |
| 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. | 6 |
| 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. | 3 |
| 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. | 3 |
| 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. | 3 |
| 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. | 3 |
| 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. | 7 |
| 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. | 7 |
| 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. | 20 |
| Phase 2: Cohort A Participants with 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. | 32 |
| Phase 2: Cohort B Participants with KRAS-mutant or KRAS-amplified 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. | 15 |
| Phase 2: Cohort C Participants with 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. | 12 |
| 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. | 9 |
| Phase 2: Cohort E Participants with gynecological cancers with alterations in the 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. | 32 |
| 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. | 14 |
| Total | 190 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 (Dose Escalation) | Complete Consent Withdrawal | 1 | 0 | 0 | 2 | 3 | 2 | 0 | 1 | 0 | 1 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 (Dose Escalation) | Death | 2 | 2 | 3 | 2 | 6 | 5 | 3 | 2 | 3 | 1 | 5 | 7 | 11 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 (Dose Escalation) | Lost to Follow-up | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 (Dose Escalation) | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 2 (Dose Expansion) | Complete Consent Withdrawal | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 1 | 3 | 2 |
| Phase 2 (Dose Expansion) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 20 | 13 | 9 | 5 | 14 | 12 |
| Phase 2 (Dose Expansion) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 |
| Phase 2 (Dose Expansion) | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 6 | 0 | 0 | 3 | 10 | 0 |
Baseline characteristics
| Characteristic | Phase 1A: Cohort 2 Dose Escalation | Phase 1A: Cohort 3 Dose Escalation | Phase 1A: Cohort 4 Dose Escalation | Phase 1A: Cohort 5 Dose Escalation | Phase 1A: Cohort 6 Dose Escalation | Phase 1A: Cohort 7 Dose Escalation | Phase 1A: Cohort 8 Dose Escalation | Phase 1A: Cohort 9 Dose Escalation | Phase 1A: Cohort 10 Dose Escalation | Phase 1A: Cohort 11 Dose Escalation | Phase 1A: Cohort 1 Dose Escalation | Phase 1A: Cohort 12 Dose Escalation | Phase 1B Dose Expansion | Phase 2: Cohort A | Phase 2: Cohort B | Phase 2: Cohort C | Phase 2: Cohort D | Phase 2: Cohort E | Phase 2: Cohort F | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized 18 - 64 | 2 Participants | 3 Participants | 5 Participants | 5 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 0 Participants | 3 Participants | 11 Participants | 14 Participants | 5 Participants | 7 Participants | 3 Participants | 16 Participants | 7 Participants | 96 Participants |
| Age, Customized 65 - 84 | 1 Participants | 0 Participants | 0 Participants | 5 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 4 Participants | 8 Participants | 18 Participants | 9 Participants | 5 Participants | 6 Participants | 16 Participants | 7 Participants | 92 Participants |
| Age, Customized >=85 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants |
| Race/Ethnicity, Customized Hispanic, Latino/a, or Spanish origin | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 4 Participants | 2 Participants | 22 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian and Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not of Hispanic, Latino/a, or Spanish origin | 3 Participants | 3 Participants | 5 Participants | 10 Participants | 5 Participants | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 7 Participants | 2 Participants | 6 Participants | 19 Participants | 30 Participants | 12 Participants | 8 Participants | 8 Participants | 25 Participants | 12 Participants | 164 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 10 Participants | 0 Participants | 4 Participants | 2 Participants | 4 Participants | 1 Participants | 21 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 3 Participants | 4 Participants | 9 Participants | 6 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 6 Participants | 3 Participants | 5 Participants | 16 Participants | 20 Participants | 12 Participants | 7 Participants | 6 Participants | 27 Participants | 11 Participants | 145 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 5 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 4 Participants | 12 Participants | 12 Participants | 10 Participants | 7 Participants | 5 Participants | 32 Participants | 6 Participants | 121 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 5 Participants | 0 Participants | 3 Participants | 8 Participants | 20 Participants | 5 Participants | 5 Participants | 4 Participants | 0 Participants | 8 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 2 / 3 | 3 / 3 | 3 / 5 | 9 / 10 | 4 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 1 / 3 | 5 / 7 | 7 / 7 | 13 / 20 | 23 / 32 | 13 / 15 | 10 / 12 | 5 / 9 | 14 / 32 | 11 / 14 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 5 / 5 | 8 / 10 | 6 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 7 / 7 | 7 / 7 | 20 / 20 | 31 / 32 | 15 / 15 | 12 / 12 | 9 / 9 | 32 / 32 | 13 / 14 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 2 / 3 | 2 / 5 | 7 / 10 | 1 / 6 | 2 / 3 | 0 / 3 | 1 / 3 | 1 / 3 | 3 / 7 | 1 / 7 | 9 / 20 | 11 / 32 | 5 / 15 | 4 / 12 | 3 / 9 | 12 / 32 | 4 / 14 |
Outcome results
Primary
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.
Time frame: Cycle 1 (cycle length = 21 days)
Population: The safety analysis set included data from all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Phase 1B Dose Expansion | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
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.
Time frame: From first dose of study drug up to 30 days after last dose (Up to 74 months)
Population: The safety analysis set included data from all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 5 Participants |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 10 Participants |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| Phase 1B Dose Expansion | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 20 Participants |
Primary
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
Time frame: Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 74 months)
Population: The efficacy analysis set included all participants who received any amount of study drug. The ORR analysis was based on participants who were in the efficacy analysis set and who had disease assessment at baseline and at least 1 follow-up disease assessment or participants who died or stopped treatment before the first scheduled disease assessment due to clinical progression or toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 12.5 percentage of participants |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 0 percentage of participants |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 8.3 percentage of participants |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 0 percentage of participants |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 12.5 percentage of participants |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | 7.1 percentage of participants |
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 327 h*ng/mL | Geometric Coefficient of Variation 3.6 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 346 h*ng/mL | Geometric Coefficient of Variation 52.9 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 358 h*ng/mL | Geometric Coefficient of Variation 209.2 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 243 h*ng/mL | Geometric Coefficient of Variation 228.9 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 1150 h*ng/mL | Geometric Coefficient of Variation 14.1 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 1430 h*ng/mL | Geometric Coefficient of Variation 60.9 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 4050 h*ng/mL | Geometric Coefficient of Variation 82.5 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 5160 h*ng/mL | Geometric Coefficient of Variation 55 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 7670 h*ng/mL | Geometric Coefficient of Variation 75.3 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 8170 h*ng/mL | Geometric Coefficient of Variation 53.5 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 1180 h*ng/mL | Geometric Coefficient of Variation 112.9 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 2470 h*ng/mL | Geometric Coefficient of Variation 116.1 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 3190 h*ng/mL | Geometric Coefficient of Variation 169.8 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 3390 h*ng/mL | Geometric Coefficient of Variation 139.3 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 3120 h*ng/mL | Geometric Coefficient of Variation 126.3 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 3420 h*ng/mL | Geometric Coefficient of Variation 113.6 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 6520 h*ng/mL | Geometric Coefficient of Variation 66.6 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 5590 h*ng/mL | Geometric Coefficient of Variation 101.3 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 5770 h*ng/mL | Geometric Coefficient of Variation 26.7 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 7930 h*ng/mL | Geometric Coefficient of Variation 37.2 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 15700 h*ng/mL | Geometric Coefficient of Variation 59 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 13500 h*ng/mL | Geometric Coefficient of Variation 47.1 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C2D1 | 25600 h*ng/mL | Geometric Coefficient of Variation 92.2 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of ASTX029 | C1D1 | 17900 h*ng/mL | Geometric Coefficient of Variation 83.1 |
Secondary
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.
Time frame: 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)
Population: The pharmacokinetics (PK) analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 277 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 20.1 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 339 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 58.4 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 361 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 222 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 618 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 11.7 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 1150 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 10 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 1410 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 61.4 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 4020 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 83 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 3530 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 104.5 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 7550 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 76.9 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 7250 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 63.7 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 1810 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 126.9 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 2490 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 108.4 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 3710 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 106 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 3360 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 140.4 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 3080 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 128.2 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 3370 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 117.8 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 6500 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 64.3 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 6430 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 71.6 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 5710 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 27.1 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 7850 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 37.1 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 15400 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 57.5 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 13400 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 46.4 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 2 Day 1 (C2D1) | 25600 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 91.9 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of ASTX029 | Cycle 1 Day 1 (C1D1) | 17800 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 83.6 |
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 262 h*ng/mL | Geometric Coefficient of Variation 18.5 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 321 h*ng/mL | Geometric Coefficient of Variation 56.1 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 347 h*ng/mL | Geometric Coefficient of Variation 215.6 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 298 h*ng/mL | Geometric Coefficient of Variation 177.3 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 1140 h*ng/mL | Geometric Coefficient of Variation 10 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 1410 h*ng/mL | Geometric Coefficient of Variation 61.5 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 4020 h*ng/mL | Geometric Coefficient of Variation 82.9 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 3530 h*ng/mL | Geometric Coefficient of Variation 104.5 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 7530 h*ng/mL | Geometric Coefficient of Variation 77.2 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 7250 h*ng/mL | Geometric Coefficient of Variation 63.7 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 1740 h*ng/mL | Geometric Coefficient of Variation 137.5 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 2430 h*ng/mL | Geometric Coefficient of Variation 116.3 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 3660 h*ng/mL | Geometric Coefficient of Variation 104.2 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 3360 h*ng/mL | Geometric Coefficient of Variation 140.4 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 1620 h*ng/mL | Geometric Coefficient of Variation 215.6 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 3340 h*ng/mL | Geometric Coefficient of Variation 116.4 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 6450 h*ng/mL | Geometric Coefficient of Variation 65.8 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 6450 h*ng/mL | Geometric Coefficient of Variation 72 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 5710 h*ng/mL | Geometric Coefficient of Variation 26.9 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 7850 h*ng/mL | Geometric Coefficient of Variation 37.1 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 13500 h*ng/mL | Geometric Coefficient of Variation 80 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 12800 h*ng/mL | Geometric Coefficient of Variation 51.2 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C2D1 | 25300 h*ng/mL | Geometric Coefficient of Variation 93.7 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of ASTX029 | C1D1 | 17800 h*ng/mL | Geometric Coefficient of Variation 83.6 |
Secondary
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.
Time frame: Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Population: The efficacy analysis set included all participants who received any amount of study drug. The DCR analysis was based on participants who were in the efficacy analysis set and who had disease assessment at baseline and at least 1 follow-up disease assessment or participants who died or stopped treatment before the first scheduled disease assessment due to clinical progression or toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 0 percentage of participants |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 0 percentage of participants |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 100 percentage of participants |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 40.0 percentage of participants |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 20.0 percentage of participants |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 16.7 percentage of participants |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 66.7 percentage of participants |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 33.3 percentage of participants |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 33.3 percentage of participants |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 33.3 percentage of participants |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 85.7 percentage of participants |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Disease Control Rate (DCR) | 42.9 percentage of participants |
| Phase 1B Dose Expansion | Phase 1: Disease Control Rate (DCR) | 30.0 percentage of participants |
Secondary
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.
Time frame: Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Population: The efficacy analysis set included all participants who received any amount of study drug. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Duration of Response (DoR) | 484.0 days |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Duration of Response (DoR) | 61.0 days |
| Phase 1B Dose Expansion | Phase 1: Duration of Response (DoR) | 252.50 days |
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. The data is reported here for the arm groups of 80 mg and 120 mg, in both fed and fasted to compare food effect. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Effect of Food on AUC0-24 of ASTX029 | C1D1 | 1810 h*ng/mL | Geometric Coefficient of Variation 126.9 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Effect of Food on AUC0-24 of ASTX029 | C2D1 | 2490 h*ng/mL | Geometric Coefficient of Variation 108.4 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Effect of Food on AUC0-24 of ASTX029 | C2D1 | 3710 h*ng/mL | Geometric Coefficient of Variation 106 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Effect of Food on AUC0-24 of ASTX029 | C1D1 | 3360 h*ng/mL | Geometric Coefficient of Variation 140.4 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Effect of Food on AUC0-24 of ASTX029 | C1D1 | 6500 h*ng/mL | Geometric Coefficient of Variation 64.3 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Effect of Food on AUC0-24 of ASTX029 | C2D1 | 6430 h*ng/mL | Geometric Coefficient of Variation 71.6 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Effect of Food on AUC0-24 of ASTX029 | C1D1 | 5710 h*ng/mL | Geometric Coefficient of Variation 27.1 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Effect of Food on AUC0-24 of ASTX029 | C2D1 | 7850 h*ng/mL | Geometric Coefficient of Variation 37.1 |
Comparison: Comparison of effect of food on AUC0-24 between Cohort 6 (fed state) and Cohort 9 (fasted state) treatment arm groups of 80 mg ASTX029 in C1D1.90% CI: [8.5, 91.2]
Comparison: Comparison of effect of food on AUC0-24 between Cohort 6 (fed state) and Cohort 9 (fasted state) treatment arm groups of 80 mg ASTX029 in C2D1.90% CI: [11.4, 132]
Comparison: Comparison of effect of food on AUC0-24 between Cohort 7 (fed state) and Cohort 10 (fasted state) treatment arm groups of 120 mg ASTX029 in C1D1.90% CI: [15.7, 222]
Comparison: Comparison of effect of food on AUC0-24 between Cohort 7 (fed state) and Cohort 10 (fasted state) treatment arm groups of 120 mg ASTX029 in C2D1.90% CI: [20.7, 108]
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. The data is reported here for the arm groups of 80 mg and 120 mg, in both fed and fasted to compare food effect. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Effect of Food on AUC0-inf of ASTX029 | C1D1 | 1180 h*ng/mL | Geometric Coefficient of Variation 112.9 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Effect of Food on AUC0-inf of ASTX029 | C2D1 | 2470 h*ng/mL | Geometric Coefficient of Variation 116.1 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Effect of Food on AUC0-inf of ASTX029 | C2D1 | 3190 h*ng/mL | Geometric Coefficient of Variation 169.8 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Effect of Food on AUC0-inf of ASTX029 | C1D1 | 3390 h*ng/mL | Geometric Coefficient of Variation 139.3 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Effect of Food on AUC0-inf of ASTX029 | C1D1 | 6520 h*ng/mL | Geometric Coefficient of Variation 66.6 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Effect of Food on AUC0-inf of ASTX029 | C2D1 | 5590 h*ng/mL | Geometric Coefficient of Variation 101.3 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Effect of Food on AUC0-inf of ASTX029 | C1D1 | 5770 h*ng/mL | Geometric Coefficient of Variation 26.7 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Effect of Food on AUC0-inf of ASTX029 | C2D1 | 7930 h*ng/mL | Geometric Coefficient of Variation 37.2 |
Comparison: Comparison of effect of food on AUC0-inf between Cohort 6 (fed state) and Cohort 9 (fasted state) treatment arm groups of 80 mg ASTX029 in C1D1.90% CI: [5.28, 61.9]
Comparison: Comparison of effect of food on AUC0-inf between Cohort 6 (fed state) and Cohort 9 (fasted state) treatment arm groups of 80 mg ASTX029 in C2D1.90% CI: [8.32, 234]
Comparison: Comparison of effect of food on AUC0-inf between Cohort 7 (fed state) and Cohort 10 (fasted state) treatment arm groups of 120 mg ASTX029 in C1D1.90% CI: [15.7, 220]
Comparison: Comparison of effect of food on AUC0-inf between Cohort 7 (fed state) and Cohort 10 (fasted state) treatment arm groups of 120 mg ASTX029 in C2D1.90% CI: [14.3, 113]
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. The data is reported here for the arm groups of 80 mg and 120 mg, in both fed and fasted to compare food effect. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Effect of Food on Cmax of ASTX029 | C1D1 | 496 ng/mL | Geometric Coefficient of Variation 127.7 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Effect of Food on Cmax of ASTX029 | C2D1 | 641 ng/mL | Geometric Coefficient of Variation 91.4 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Effect of Food on Cmax of ASTX029 | C2D1 | 1710 ng/mL | Geometric Coefficient of Variation 124.4 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Effect of Food on Cmax of ASTX029 | C1D1 | 1490 ng/mL | Geometric Coefficient of Variation 141.7 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Effect of Food on Cmax of ASTX029 | C1D1 | 2840 ng/mL | Geometric Coefficient of Variation 30.8 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Effect of Food on Cmax of ASTX029 | C2D1 | 1860 ng/mL | Geometric Coefficient of Variation 55.8 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Effect of Food on Cmax of ASTX029 | C1D1 | 2060 ng/mL | Geometric Coefficient of Variation 49.5 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Effect of Food on Cmax of ASTX029 | C2D1 | 2360 ng/mL | Geometric Coefficient of Variation 40.9 |
Comparison: Comparison of effect of food on Cmax between Cohort 6 (fed state) and Cohort 9 (fasted state) treatment arm groups of 80 mg ASTX029 in C1D1.90% CI: [5.62, 54.3]
Comparison: Comparison of effect of food on Cmax between Cohort 6 (fed state) and Cohort 9 (fasted state) treatment arm groups of 80 mg ASTX029 in C2D1.90% CI: [12, 99.4]
Comparison: Comparison of effect of food on Cmax between Cohort 7 (fed state) and Cohort 10 (fasted state) treatment arm groups of 120 mg ASTX029 in C1D1.90% CI: [17.6, 299]
Comparison: Comparison of effect of food on Cmax between Cohort 7 (fed state) and Cohort 10 (fasted state) treatment arm groups of 120 mg ASTX029 in C1D1.90% CI: [29.1, 181]
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. The data is reported here for the arm groups of 80 mg and 120 mg, in both fed and fasted to compare food effect. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Effect of Food on Tmax of ASTX029 | C1D1 | 3.03 hours |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Effect of Food on Tmax of ASTX029 | C2D1 | 2.48 hours |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Effect of Food on Tmax of ASTX029 | C2D1 | 1.02 hours |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Effect of Food on Tmax of ASTX029 | C1D1 | 1.00 hours |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Effect of Food on Tmax of ASTX029 | C1D1 | 1.00 hours |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Effect of Food on Tmax of ASTX029 | C2D1 | 3.00 hours |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Effect of Food on Tmax of ASTX029 | C1D1 | 1.88 hours |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Effect of Food on Tmax of ASTX029 | C2D1 | 2.1 hours |
Comparison: Comparison of effect of food on Tmax between Cohort 6 (fed state) and Cohort 9 (fasted state) treatment arm groups of 80 mg ASTX029 in C1D1.p-value: 0.038867190% CI: [-5.216, -0.083]Wilcoxon (Mann-Whitney)
Comparison: Comparison of effect of food on Tmax between Cohort 6 (fed state) and Cohort 9 (fasted state) treatment arm groups of 80 mg ASTX029 in C2D1.p-value: 0.479500190% CI: [-0.917, 5.15]Wilcoxon (Mann-Whitney)
Comparison: Comparison of effect of food on Tmax between Cohort 7 (fed state) and Cohort 10 (fasted state) treatment arm groups of 120 mg ASTX029 in C1D1.p-value: 0.827259390% CI: [-2.467, 0.95]Wilcoxon (Mann-Whitney)
Comparison: Comparison of effect of food on Tmax between Cohort 7 (fed state) and Cohort 10 (fasted state) treatment arm groups of 120 mg ASTX029 in C2D1.p-value: 0.512690890% CI: [-6.45, 3.5]Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 2.42 hours | Geometric Coefficient of Variation 42.1 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 3.37 hours | Geometric Coefficient of Variation 119.7 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 1.63 hours | Geometric Coefficient of Variation 18.7 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 1.85 hours | Geometric Coefficient of Variation 64.8 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 4.42 hours | Geometric Coefficient of Variation 1.8 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 4.98 hours | Geometric Coefficient of Variation 31.5 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 3.75 hours | Geometric Coefficient of Variation 26.9 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 3.61 hours | Geometric Coefficient of Variation 13.5 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 4.11 hours | Geometric Coefficient of Variation 15.9 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 3.84 hours | Geometric Coefficient of Variation 21.8 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 2.08 hours | Geometric Coefficient of Variation 102.4 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 2.58 hours | Geometric Coefficient of Variation 95.1 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 1.01 hours | Geometric Coefficient of Variation 11.6 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 4.28 hours | Geometric Coefficient of Variation 11.6 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 5.68 hours | Geometric Coefficient of Variation 31.7 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 3.13 hours | Geometric Coefficient of Variation 276.4 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 3.30 hours | Geometric Coefficient of Variation 74.7 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 4.67 hours | Geometric Coefficient of Variation 24.1 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 4.00 hours | Geometric Coefficient of Variation 13.6 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 3.88 hours | Geometric Coefficient of Variation 25.6 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 3.80 hours | Geometric Coefficient of Variation 47.2 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 3.92 hours | Geometric Coefficient of Variation 40.9 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C2D1 | 1.28 hours | Geometric Coefficient of Variation 72.1 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Elimination Half-Life (T1/2) of ASTX029 | C1D1 | 3.71 hours | Geometric Coefficient of Variation 32.9 |
Secondary
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.
Time frame: 4 hours post-dose on Day 8 of Cycle 2 (Cycle length = 21 days)
Population: Pharmacodynamics analysis set included in the pharmacodynamic and biomarker analyses if they have received study drug and their samples were successfully collected and analyzed. Overall number of participants analyzed is the number of participants with data available for analysis. The data for this outcome measure was collected and analyzed for Phase 1B Dose Expansion cohort only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Inhibition of Phosphorylated Ribosomal S6 Kinase (pRSK) Protein in Response to ASTX029 Treatment in Tumor Biopsies as Assessed by H Score | 181.6 score on a scale | Standard Deviation 172.31 |
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 109 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 48.5 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 143 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 177.8 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 217 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 165.4 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 107 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 119.2 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 469 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 9.5 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 598 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 111 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 1650 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 56.8 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 903 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 228.8 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 1830 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 177.6 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 1850 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 66.7 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 496 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 127.7 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 641 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 91.4 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 1710 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 124.4 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 1490 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 141.7 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 742 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 301.5 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 2330 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 130.8 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 2840 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 30.8 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 1860 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 55.8 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 2060 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 49.5 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 2360 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 40.9 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 5350 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 78.7 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 5240 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 61 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C2D1 | 8070 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 50.7 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Maximum Observed Plasma Concentration (Cmax) of ASTX029 | C1D1 | 6040 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 58.4 |
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 4.38 ng/mL | Geometric Coefficient of Variation 86.7 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 1.45 ng/mL | Geometric Coefficient of Variation 173.2 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 23.4 ng/mL | Geometric Coefficient of Variation 127.8 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 19.3 ng/mL | Geometric Coefficient of Variation 149.7 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 18.1 ng/mL | Geometric Coefficient of Variation 39.7 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 7.88 ng/mL | Geometric Coefficient of Variation 79.3 |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 68.1 ng/mL | Geometric Coefficient of Variation 128.8 |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 8.68 ng/mL | Geometric Coefficient of Variation 64 |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 20.1 ng/mL | Geometric Coefficient of Variation 114.7 |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 85.3 ng/mL | Geometric Coefficient of Variation 206.9 |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 188 ng/mL | Geometric Coefficient of Variation 194.3 |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Minimum Plasma Concentration (Cmin) of ASTX029 | 168 ng/mL | Geometric Coefficient of Variation 85.6 |
Secondary
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.
Time frame: Up to 82 months
Population: The efficacy analysis set included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Overall Survival (OS) | 13.5 months |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Overall Survival (OS) | 4.5 months |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Overall Survival (OS) | 10.2 months |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Overall Survival (OS) | 3.8 months |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Overall Survival (OS) | 2.1 months |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Overall Survival (OS) | 11.3 months |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Overall Survival (OS) | 8.7 months |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Overall Survival (OS) | 2.0 months |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Overall Survival (OS) | 10.9 months |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Overall Survival (OS) | NA months |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Overall Survival (OS) | 14.8 months |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Overall Survival (OS) | 2.5 months |
| Phase 1B Dose Expansion | Phase 1: Overall Survival (OS) | 15.1 months |
Secondary
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.
Time frame: Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Population: The efficacy analysis set included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 1.3 months |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 1.2 months |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 8.1 months |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 2.0 months |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 1.2 months |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 1.3 months |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 3.0 months |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 1.1 months |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 1.3 months |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 2.3 months |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 3.0 months |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Progression Free Survival (PFS) | 2.5 months |
| Phase 1B Dose Expansion | Phase 1: Progression Free Survival (PFS) | 1.4 months |
Secondary
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.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 1.08 hours |
| Phase 1A: Cohort 1 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 0.53 hours |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 0.50 hours |
| Phase 1A: Cohort 2 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 1.00 hours |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 0.55 hours |
| Phase 1A: Cohort 3 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 0.50 hours |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 0.50 hours |
| Phase 1A: Cohort 4 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 2.52 hours |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 0.55 hours |
| Phase 1A: Cohort 5 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 0.71 hours |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 3.03 hours |
| Phase 1A: Cohort 6 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 2.48 hours |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 1.02 hours |
| Phase 1A: Cohort 7 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 1.00 hours |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 1.07 hours |
| Phase 1A: Cohort 8 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 1.52 hours |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 1.00 hours |
| Phase 1A: Cohort 9 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 3.00 hours |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 1.88 hours |
| Phase 1A: Cohort 10 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 2.1 hours |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 2.02 hours |
| Phase 1A: Cohort 11 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 1.97 hours |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C2D1 | 1.90 hours |
| Phase 1A: Cohort 12 Dose Escalation | Phase 1: Time to Reach Maximum Concentration (Tmax) of ASTX029 | C1D1 | 2.03 hours |
Secondary
Phase 2: AUC0-24 of ASTX029
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | C1D1 | 12200 h*ng/mL | Geometric Coefficient of Variation 69.1 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | Cycle 3 Day 1 (C3D1) | 11600 h*ng/mL | Geometric Coefficient of Variation 76.1 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | C1D1 | 13000 h*ng/mL | Geometric Coefficient of Variation 57.2 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | Cycle 3 Day 1 (C3D1) | 27600 h*ng/mL | Geometric Coefficient of Variation 47.3 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | C1D1 | 9570 h*ng/mL | Geometric Coefficient of Variation 80.3 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | Cycle 3 Day 1 (C3D1) | 11500 h*ng/mL | — |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | C1D1 | 8730 h*ng/mL | Geometric Coefficient of Variation 100 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | Cycle 3 Day 1 (C3D1) | 12800 h*ng/mL | Geometric Coefficient of Variation 36.2 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | C1D1 | 12000 h*ng/mL | Geometric Coefficient of Variation 83.3 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | Cycle 3 Day 1 (C3D1) | 12300 h*ng/mL | Geometric Coefficient of Variation 88.7 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | C1D1 | 13400 h*ng/mL | Geometric Coefficient of Variation 71.3 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: AUC0-24 of ASTX029 | Cycle 3 Day 1 (C3D1) | 15300 h*ng/mL | Geometric Coefficient of Variation 52.4 |
Secondary
Phase 2: AUC0-inf of ASTX029
Data for Auc0-inf was collected and analyzed for C1D1 only.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: AUC0-inf of ASTX029 | 12500 h*ng/mL | Geometric Coefficient of Variation 66.6 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: AUC0-inf of ASTX029 | 17100 h*ng/mL | Geometric Coefficient of Variation 60.4 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: AUC0-inf of ASTX029 | 10700 h*ng/mL | Geometric Coefficient of Variation 103 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: AUC0-inf of ASTX029 | 11800 h*ng/mL | Geometric Coefficient of Variation 62.5 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: AUC0-inf of ASTX029 | 12500 h*ng/mL | Geometric Coefficient of Variation 74.5 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: AUC0-inf of ASTX029 | 13300 h*ng/mL | Geometric Coefficient of Variation 67.5 |
Secondary
Phase 2: AUC0-last of ASTX029
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C1D1 | 12300 h*ng/mL | Geometric Coefficient of Variation 70.4 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C3D1 | 8090 h*ng/mL | Geometric Coefficient of Variation 214.2 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C1D1 | 15000 h*ng/mL | Geometric Coefficient of Variation 68.5 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C3D1 | 13600 h*ng/mL | Geometric Coefficient of Variation 114.5 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C1D1 | 7800 h*ng/mL | Geometric Coefficient of Variation 81.7 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C3D1 | 1960 h*ng/mL | Geometric Coefficient of Variation 369.9 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C1D1 | 8730 h*ng/mL | Geometric Coefficient of Variation 100 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C3D1 | 11700 h*ng/mL | Geometric Coefficient of Variation 31.5 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C1D1 | 11500 h*ng/mL | Geometric Coefficient of Variation 80.3 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C3D1 | 10400 h*ng/mL | Geometric Coefficient of Variation 86.4 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C1D1 | 12700 h*ng/mL | Geometric Coefficient of Variation 66.9 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: AUC0-last of ASTX029 | C3D1 | 14000 h*ng/mL | Geometric Coefficient of Variation 52.1 |
Secondary
Phase 2: Cmax of ASTX029
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Cmax of ASTX029 | C1D1 | 4430 ng/mL | Geometric Coefficient of Variation 70.9 |
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Cmax of ASTX029 | C3D1 | 3280 ng/mL | Geometric Coefficient of Variation 179.3 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Cmax of ASTX029 | C1D1 | 5930 ng/mL | Geometric Coefficient of Variation 81.3 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Cmax of ASTX029 | C3D1 | 4730 ng/mL | Geometric Coefficient of Variation 150.7 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Cmax of ASTX029 | C1D1 | 2890 ng/mL | Geometric Coefficient of Variation 97.7 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Cmax of ASTX029 | C3D1 | 780 ng/mL | Geometric Coefficient of Variation 464.1 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Cmax of ASTX029 | C1D1 | 2840 ng/mL | Geometric Coefficient of Variation 239.4 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Cmax of ASTX029 | C3D1 | 5090 ng/mL | Geometric Coefficient of Variation 43.5 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Cmax of ASTX029 | C1D1 | 4660 ng/mL | Geometric Coefficient of Variation 113.6 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Cmax of ASTX029 | C3D1 | 4410 ng/mL | Geometric Coefficient of Variation 110.4 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Cmax of ASTX029 | C1D1 | 5620 ng/mL | Geometric Coefficient of Variation 65.7 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Cmax of ASTX029 | C3D1 | 4860 ng/mL | Geometric Coefficient of Variation 66.8 |
Secondary
Phase 2: Cmin of ASTX029
Data for Cmin was calculated and analyzed for C3D1 only.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Cmin of ASTX029 | 189 ng/mL | Geometric Coefficient of Variation 181 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Cmin of ASTX029 | 260 ng/mL | Geometric Coefficient of Variation 95.5 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Cmin of ASTX029 | 81.7 ng/mL | Geometric Coefficient of Variation 102 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Cmin of ASTX029 | 144 ng/mL | Geometric Coefficient of Variation 78.2 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Cmin of ASTX029 | 205 ng/mL | Geometric Coefficient of Variation 104.9 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Cmin of ASTX029 | 246 ng/mL | Geometric Coefficient of Variation 67.6 |
Secondary
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.
Time frame: Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Population: The efficacy analysis set included all participants who received any amount of study drug. The DCR analysis was based on participants who were in the efficacy analysis set and who had disease assessment at baseline and at least 1 follow-up disease assessment or participants who died or stopped treatment before the first scheduled disease assessment due to clinical progression or toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Disease Control Rate | 65.6 percentage of participants |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Disease Control Rate | 60.0 percentage of participants |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Disease Control Rate | 41.7 percentage of participants |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Disease Control Rate | 77.8 percentage of participants |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Disease Control Rate | 68.8 percentage of participants |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Disease Control Rate | 42.9 percentage of participants |
Secondary
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.
Time frame: Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Population: The efficacy analysis set included all participants who received any amount of study drug. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Duration of Response | 193.00 days |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Duration of Response | 144.00 days |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Duration of Response | 189.50 days |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Duration of Response | 750.00 days |
Secondary
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.
Time frame: Up to 82 months
Population: The efficacy analysis set included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Overall Survival | 8.0 months |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Overall Survival | 4.9 months |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Overall Survival | 6.1 months |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Overall Survival | 11.6 months |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Overall Survival | 11.2 months |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Overall Survival | 9.9 months |
Secondary
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.
Time frame: Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months)
Population: The efficacy analysis set included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Progression Free Survival | 2.8 months |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Progression Free Survival | 2.8 months |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Progression Free Survival | 1.7 months |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Progression Free Survival | 8.0 months |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Progression Free Survival | 3.5 months |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Progression Free Survival | 2.0 months |
Secondary
Phase 2: T1/2 of ASTX029
Data for T1/2 was collected and analyzed for C1D1 only.
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: T1/2 of ASTX029 | 2.68 hours | Geometric Coefficient of Variation 68.8 |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: T1/2 of ASTX029 | 3.45 hours | Geometric Coefficient of Variation 52 |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: T1/2 of ASTX029 | 3.79 hours | Geometric Coefficient of Variation 19.1 |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: T1/2 of ASTX029 | 3.73 hours | Geometric Coefficient of Variation 12.2 |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: T1/2 of ASTX029 | 3.64 hours | Geometric Coefficient of Variation 43.2 |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: T1/2 of ASTX029 | 3.39 hours | Geometric Coefficient of Variation 48.2 |
Secondary
Phase 2: Tmax of ASTX029
Time frame: 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)
Population: The PK analysis set included all participants who had received study drug with available plasma concentrations and PK parameters for ASTX029. Overall number of participants analyzed is the number of participants with data available for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Tmax of ASTX029 | C3D1 | 2.00 hours |
| Phase 1A: Cohort 1 Dose Escalation | Phase 2: Tmax of ASTX029 | C1D1 | 2.03 hours |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Tmax of ASTX029 | C3D1 | 2.03 hours |
| Phase 1A: Cohort 2 Dose Escalation | Phase 2: Tmax of ASTX029 | C1D1 | 1.95 hours |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Tmax of ASTX029 | C3D1 | 2.03 hours |
| Phase 1A: Cohort 3 Dose Escalation | Phase 2: Tmax of ASTX029 | C1D1 | 2.90 hours |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Tmax of ASTX029 | C1D1 | 2.07 hours |
| Phase 1A: Cohort 4 Dose Escalation | Phase 2: Tmax of ASTX029 | C3D1 | 1.90 hours |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Tmax of ASTX029 | C1D1 | 2.00 hours |
| Phase 1A: Cohort 5 Dose Escalation | Phase 2: Tmax of ASTX029 | C3D1 | 2.00 hours |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Tmax of ASTX029 | C1D1 | 2.00 hours |
| Phase 1A: Cohort 6 Dose Escalation | Phase 2: Tmax of ASTX029 | C3D1 | 1.97 hours |