Clinical Trials /

Study of ASTX029 in Subjects With Advanced Solid Tumors

NCT03520075

Description:

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 subjects with advanced solid malignancies who are not candidates for approved or available therapies.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ASTX029-01
  • NCT ID: NCT03520075

Conditions

  • Solid Tumor, Adult

Interventions

DrugSynonymsArms
ASTX029Phase 1 Regimen 1

Purpose

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 subjects 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 subjects. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 Regimen 1ExperimentalDose escalation and expansion: Regimen 1: ASTX029 orally once a day for 21 days of each 21-day cycle.
  • ASTX029
Phase 1 Regimen 2ExperimentalDose escalation and expansion: Regimen 2: ASTX029 orally once a day for 14 days of each 21-day cycle.
  • ASTX029
Phase 2ExperimentalASTX029 at the RP2D of the selected dosing regimen identified in Phase 1 to subjects with tumors characterized by gene aberrations in the MAPK signal pathway that may confer sensitivity to ASTX029.
  • ASTX029

Eligibility Criteria

        Inclusion Criteria:

        Subjects 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. 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 (except in the potential food-effect
             cohort) and in the Phase 2 portion of the protocol, subjects must also have documented
             gene alterations in the MAPK pathway as detailed in the protocol.

          4. In Phase 1 Part B (except in the potential food-effect cohort) 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 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 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 ≥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 as detailed in the protocol) must not be pregnant or breastfeeding
             and must have a negative pregnancy test at screening. Women of child-bearing potential
             and men with female partners of child-bearing potential must agree to practice 2
             highly effective contraceptive measures (as described in the protocol) during the
             study and for at least 3 months after completing treatment and must agree not to
             become pregnant or father a child while receiving study treatment and for at least 3
             months after completing treatment.

        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:

               1. Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered
                  treatment-related toxicities (excepting alopecia) not stabilized or resolved to
                  ≤Grade 1.

               2. Monoclonal antibodies within 4 weeks prior and any encountered treatment-related
                  toxicities not 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.

          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:

               1. Abnormal left ventricular ejection fraction (<50%) on echocardiogram or
                  multiple-gated acquisition 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 block, presence of cardiac
                  pacemaker or defibrillator, or other significant arrhythmias.

               5. Screening 12-lead electrocardiogram 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 infection or seropositive results
             consistent with active hepatitis B virus or active hepatitis C virus 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:

               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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety (Phase 1) - Dose-limiting toxicities including incidence of Treatment-Emergent Adverse Events
Time Frame:End of each dosing cycle (Day 21 of 21-day cycle)
Safety Issue:
Description:Number of subjects with dose-limiting toxicities

Secondary Outcome Measures

Measure:Pharmacokinetic profile of ASTX029 - AUC
Time Frame:Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2
Safety Issue:
Description:1) Area under the time-concentration curve
Measure:Pharmacokinetic profile of ASTX029 - Cmax
Time Frame:Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2
Safety Issue:
Description:2) Maximum plasma concentration
Measure:Pharmacokinetic profile of ASTX029 - Cmin
Time Frame:Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2
Safety Issue:
Description:3) Minimum plasma concentration
Measure:Pharmacokinetic profile of ASTX029 - Tmax
Time Frame:Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2
Safety Issue:
Description:4) Time to reach maximum concentration
Measure:Pharmacokinetic profile of ASTX029 - Half-life
Time Frame:Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2
Safety Issue:
Description:5) Elimination half-life
Measure:Pharmacokinetic profile of ASTX029 - Metabolites
Time Frame:Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2
Safety Issue:
Description:6) Analysis of ASTX029 metabolites if applicable
Measure:Efficacy - DOR
Time Frame:Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year
Safety Issue:
Description:Duration of response
Measure:Efficacy - DCR
Time Frame:Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year
Safety Issue:
Description:Disease control rate
Measure:Efficacy - PFS
Time Frame:Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year
Safety Issue:
Description:Progressive-free survival
Measure:Efficacy - OS
Time Frame:Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year
Safety Issue:
Description:Overall survival
Measure:Target engagement in tumor tissues - pRSK
Time Frame:Day 8 of Cycle 2
Safety Issue:
Description:Inhibition of phosphorylated ribosomal s6 kinase protein in response to ASTX029 treatment in fresh tumor biopsies

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astex Pharmaceuticals

Trial Keywords

  • Neoplasms
  • Solid Tumors
  • Antineoplastic Agents
  • MAPK
  • ERK

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