A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in Subjects With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 192
- 试验地点
- 31
- 主要终点
- Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must fulfill all of the following inclusion criteria.
- •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.
- •Men or women 18 years of age or older.
- •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.
- •In Phase 1 Part B of the protocol, participants must have disease lesions that are amenable to biopsy.
- •In the Phase 2 portion of the protocol, participants must have measurable disease according to RECIST v1.
- •Eastern Cooperative Oncology Group performance status 0 to
- •Acceptable organ function as evidenced by the following laboratory data:
- •Aspartate aminotransferase (AST) and alanine aminotransferase ≤2×upper limit of normal (ULN) or ≤3 ULN in the presence of liver metastases.
- •Total serum bilirubin ≤1.5×ULN.
- •Absolute neutrophil count (ANC) ≥1500 cells/mm
- •Platelet count ≥100,000 cells/mm
- •Calculated creatinine clearance (by the standard Cockcroft Gault formula) of ≥50 mL/min or glomerular filtration rate of ≥50 mL/min.
- •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.
- •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.
排除标准
- •Hypersensitivity to ASTX029 or excipients of the drug product.
- •Poor medical risk in the investigator's opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.
- •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 ASTX
- •Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX029), as follows:
- •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
- •Monoclonal antibodies within 4 weeks prior. Any encountered treatment-related toxicities not stabilized or resolved to ≤Grade
- •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
- •Prior treatment with extracellular signal-regulated kinase (ERK) inhibitors.
- •History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:
- •Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.
- •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.
- •Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days).
- •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.
- •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.)
- •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.
- •Known brain metastases, unless previously treated and stable for at least 3 months with or without steroids.
- •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.
- •History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including:
- •Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus) or
- •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.
研究组 & 干预措施
Phase 1A: Cohort 1 Dose Escalation
Participants received ASTX029 10 milligrams (mg), powder in bottle (PiB), orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months, under fed state.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
Phase 2: Cohort A
Participants with neuroblastoma RAS (NRAS)-mutant melanoma received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months.
干预措施: ASTX029 (Drug)
Phase 2: Cohort B
Participants with Kirsten RAS (KRAS)-mutant or KRAS-amplified non-small cell lung cancer (NSCLC) received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months.
干预措施: ASTX029 (Drug)
Phase 2: Cohort C
Participants with B isoform of RAF kinase (BRAF) V600-mutant cancers (non-colorectal cancers) received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
Phase 2: Cohort E
Participants with gynecological cancers with alterations in the mitogen-activated protein kinase (MAPK) pathway received ASTX029 200 mg, tablets, orally, once daily, on Days 1-21 of each 21-day cycle, up to median duration of 1.6 months.
干预措施: ASTX029 (Drug)
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.
干预措施: ASTX029 (Drug)
结局指标
主要结局
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: 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)
时间窗: 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
时间窗: 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
次要结局
- 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))
- 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))
- 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))
- 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 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))
- 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))
- 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))
- 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))
- 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))
- Phase 2: Overall Survival(Up to 82 months)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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 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))
- Phase 1: Overall Survival (OS)(Up to 82 months)
- 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))
- 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))
- 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: Duration of Response(Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months))
- Phase 1: Duration of Response (DoR)(Every 2 cycles for the first 4 cycles and then every 4 cycles thereafter until disease progression (Up to 82 months))
- Phase 2: AUC0-24 of ASTX029(Pre-dose on Day 1 of Cycles 1, and 3; at 0.5,1, 2, 3, 4, 6, and 8 hours post-dose on Day 1 of Cycle 1, and at 0.5,1, 2, 4, and 8 hours post-dose on Day 1 of Cycle 3 (Cycle length = 21 days))
- Phase 2: 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))
- 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))