A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in Subjects With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- ASTX029
- Conditions
- Solid Tumor, Adult
- Sponsor
- Taiho Oncology, Inc.
- Enrollment
- 192
- Locations
- 31
- Primary Endpoint
- Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
- Status
- Completed
- Last Updated
- 10 months ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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.
Arms & Interventions
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
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.
Intervention: ASTX029
Outcomes
Primary Outcomes
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
Time Frame: 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)
Time Frame: 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
Time Frame: 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 Outcomes
- 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))