Advanced Solid Tumors MedDRA version: 21.1 Level: LLT Classification code 10065147 Term: Malignant solid tumor System Organ Class: 100000004864 MedDRA version: 21.1 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 100000004864 MedDRA version: 21.1 Level: LLT Classification code 10053571 Term: Melanoma System Organ Class: 100000004864 MedDRA version: 21.1 Level: LLT Classification code 10029514 Term: Non-small cell lung cancer NOS System Organ Class: 100000004864
Conditions
Interventions
Product Name: ASTX029
Pharmaceutical Form: Tablet
INN or Proposed INN: ASTX029
Current Sponsor code: ASTX029
Other descriptive name: AT35029, AT35029X free base, AT35029W for the hydrate, AP-0000055,
Sponsors
Astex Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1) Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed. 2) Men or women 18 years of age or older. 3) Subjects with histologically or cytologically confirmed advanced solid tumors that are metastatic or unresectable, who are refractory or have relapsed after treatment with available therapies or for whom standard life-prolonging measures or approved therapies are not available. In Phase 1 Part B and in the Phase 2 portion of the protocol, subjects must also have documented gene alterations in the MAPK pathway as detailed in Section 4.1.2 and Table 2. 4) In Phase 1 Part B of the protocol, subjects must have disease lesions that are amenable to biopsy. 5) In the Phase 2 portion of the protocol, subjects must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 6) Eastern Cooperative Oncology Group performance status 0 to 2. 7) Acceptable organ function, as evidenced by the following laboratory data: a) AST and alanine aminotransferase (ALT) =2×upper limit of normal (ULN) or =3 ULN in the presence of liver metastases. b) Total serum bilirubin =1.5×ULN. c) Absolute neutrophil count (ANC) =1500 cells/mm3 . d) Platelet count =100,000 cells/mm3 . e) Calculated creatinine clearance (by the standard Cockcroft-Gault formula) of =50 mL/min or glomerular filtration rate of =50 mL/min. 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 (urine or serum as required by local regulations) within 24 hours before the first dose of study treatment. Women of child-bearing potential must agree to the following during the treatment period and for 5 half-lives of ASTX029 or metabolite plus 30 days after receipt of the last dose of study treatment: a) Refrain from donating eggs (ova, oocytes) for the purpose of reproduction. b) Use a contraceptive method that is highly effective with a failure rate of =65 years) yes F.1.3.1 Number of subjects for this age range 50
Exclusion criteria
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 subject safety or the integrity of study outcomes or interfere with the absorption or metabolism of ASTX029. 4) Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX029), as follows: a) Cytotoxic chemotherapy or radiotherapy within 3 weeks prior. Palliative radiotherapy to a single lesion within 2 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) not stabilized or resolved to =Grade 1. b) Monoclonal antibodies or biologics within 4 weeks prior. Any encountered treatment related toxicities not stabilized or resolved to =Grade 1. c) Molecularly targeted drug or other investigational drugs, without the potential for delayed toxicity, within 4 weeks of the first dose of study treatment or 5 half-lives (minimum 14 days), whichever is shorter. Any encountered treatment-related toxicities (excepting alopecia) not stabilized or resolved to =Grade 1. 5) Prior treatment with ERK inhibitors. 6) History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions: a) Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan. b) Congestive cardiac failure of =Grade 3 severity according to New York Heart Association (NYHA) functional classification defined as patients with marked limitation of activity and who are comfortable only at rest. c) Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days). d) History or evidence of long QT interval corrected for heart rate (QTc), ventricular arrhythmias including ventricular bigeminy, complete left bundle branch block, clinically significant bradyarrhythmias such as sick sinus syndrome, second- and third-degree atrioventricular (AV) block, presence of cardiac pacemaker or defibrillator, or other significant arrhythmias. e) Screening 12-lead ECG with measurable QTc interval of =470 msec. (Fridericia's formula should be used to calculate the QTc interval throughout the study.) 7) Known history of human immunodeficiency virus (HIV) infection or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection. 8) Known brain metastases, unless previously treated and stable for at least 3 months with or without steroids. 9) Known significant mental illness or other conditions, such as active alcohol or other substance abuse that, in the opinion of the investigator, predispose the subject to high risk of noncompliance with the protocol treatment or assessments. 10) History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including: a) Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus) or b) Visible retinal pathology as assessed by ophthalmic examination at screening that is considered a risk factor for RVO or CSR such as: • Evidence of optic disc cupping or • Evidence of new visual
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Phase 1 (Parts A and B): To assess safety and to identify the MTD, the RP2D, and the recommended dosing regimen of ASTX029. • Phase 2: To assess preliminary clinical activity, as determined by ORR in tumors characterized by gene aberrations in the MAPK signal pathway that may confer sensitivity to ASTX029;Secondary Objective: • To determine the PK profile of ASTX029 including the food effect on PK parameters. • To evaluate other clinical activity parameters, such as duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). • To evaluate relevant pharmacodynamic markers and target engagement (ie, phosphorylated ribosomal s6 kinase [pRSK] inhibition) in tumor biopsies. ;Primary end point(s): • Phase 1: Incidences of DLTs and AEs to determine the MTD of up to 2 dosing regimens of ASTX029 and the RP2D and regimen to be taken to Phase 2. • Phase 2: Clinical activity assessed by ORR according to RECIST v1.1 criteria.;Timepoint(s) of evaluation of this end point: REGIMEN 1 Incidence of DLTs and AES: Cycle 1 and 2: Days 1, 2, 8 and 15, >/=Cycle 3: Day 1, at treatment termination and at 30-day Safety Follow-up visit Clinical activity: At screening, at the end of every 2 cycles (±7 days) for the first 4 cycles and then every 4 cycles (±1 cycle) thereafter REGIMEN 2 Incidence of DLTs and AES: Cycle 1: Days 1, 2, 8, 14 and 15, Cycle 2: Days 1, 8 and 15 >/=Cycle 3: Day 1, at treatment termination and at 30-day Safety Follow-up visit | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): REGIMEN 1 • PK parameters of ASTX029, including AUC, Cmax, minimum concentration (Cmin), time to reach maximum concentration (Tmax), elimination half-life (t½), food effect on ASTX029 PK parameters, and other secondary PK parameters of ASTX029 if data permit; analysis of ASTX029 metabolites if applicable. • Inhibition of pRSK protein in response to ASTX029 treatment in tumor biopsies. • PFS. • OS. • DCR. • DOR.;Timepoint(s) of evaluation of this end point: REGIMEN 1- Pharmacokinetics: Cycle 1 and 2: Days 1, and 2, >/=Cycle 3: Day 1 - tumor biopsies: during screening and on Day 8 of cycle 2 - PFS, OS, DCR, DOR: At screening, at the end of every 2 cycles (±7 days) for the first 4 cycles and then every 4 cycles (±1 cycle) thereafter REGIMEN 2 Pharmacokinetics: Cycle 1: Days 1, 2, 14 and 15 - >/=Cycle 3: Day 1 - tumor biopsies: during screening and on Day 8 of cycle 2 - PFS, OS, DCR, DOR: At screening, at the end of every 2 cycles (±7 days) for the first 4 cycles and then every 4 cycles (±1 cycle) thereafter | — |
Countries
France, Spain, United Kingdom, United States
Contacts
Public ContactASTX029-01 Clinical Operations
Astex Pharmaceuticals, Inc.
Outcome results
None listed