Clinical Trials /

Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53

NCT03975387

Description:

Study ASTX295-01 is a first in human Phase 1/2 open-label study of the safety, pharmacokinetics, and preliminary activity of ASTX295 in subjects with wild-type TP53 advanced solid tumors. Phase 1 is a dose escalation and dose expansion study design followed by a Phase 2 study.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53
  • Official Title: Phase 1/2 Open-Label Study of the Safety, Pharmacokinetics, and Preliminary Activity of ASTX295 in Subjects With Wild-Type TP53 Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: ASTX295-01
  • NCT ID: NCT03975387

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
ASTX295ASTX295

Purpose

Study ASTX295-01 is a first in human Phase 1/2 open-label study of the safety, pharmacokinetics, and preliminary activity of ASTX295 in subjects with wild-type TP53 advanced solid tumors. Phase 1 is a dose escalation and dose expansion study design followed by a Phase 2 study.

Detailed Description

      ASTX295 is a synthetic small molecule that acts as an antagonist of Murine Double Minute 2
      (MDM2; human homolog also known as HDM2). Study ASTX295-01 is a Phase 1/2 first in human
      (FIH) study with ASTX295 in subjects who are refractory or have relapsed after treatment with
      standard of care therapies, or for whom standard life-prolonging measures or approved
      therapies are not available.

      Phase 1 is composed of Phase 1a and 1b, a dose escalation stage followed by a dose expansion
      stage, respectively. Phase 1 is intended to identify the recommended dose for expansion (RDE)
      and ultimately the recommended Phase 2 dose (RP2D).
    

Trial Arms

NameTypeDescriptionInterventions
ASTX295Experimental
  • ASTX295

Eligibility Criteria

        Inclusion Criteria:

        Age

          1. Participant must be 18 years of age or older, at the time of signing the informed
             consent.

             Type of Participant and Disease Characteristics

          2. Have histologically or cytologically confirmed advanced solid tumors that are
             metastatic or unresectable and are refractory or have relapsed after treatment with
             standard available therapies or for whom standard life-prolonging measures are not
             available.

          3. Documented wild-type TP53 gene status.

          4. Have an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 2.

          5. Acceptable bone marrow function, as evidenced by the following laboratory data:

               1. Absolute neutrophil count (ANC) ≥1500 cells/mm3

               2. Platelet count ≥100,000 cells/mm3

               3. Hemoglobin >9 g/dL

          6. Adequate hepatic function as evidenced by:

               1. Serum total bilirubin ≤1.5 × upper limit of normal (ULN).

               2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×upper
                  limit of normal (ULN) (≤ 3 ULN in the presence of liver metastases).

               3. Serum creatinine ≤1.5 × ULN OR calculated creatinine clearance (by the standard
                  Cockcroft-Gault formula) of ≥50 mL/min or measured glomerular filtration rate of
                  ≥50 mL/min.

             Sex

          7. Participant can be male or female

             Informed Consent

          8. Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in this
             protocol, and willing to participate in the study.

             Participants are eligible to be included in Phase 1 Part B of the study only if all of
             the following additional criteria apply:

          9. In Phase 1 Part B (dose expansion) of the protocol, subjects must have disease lesions
             that are amenable to biopsy and must agree and be able to undergo a pre- and on-
             treatment biopsy.

             Participants are eligible to be included in Phase 2 of the study only if all of the
             following additional criteria apply:

         10. There is confirmed availability of sufficient tumor specimen either from archival
             formalin-fixed, paraffin embedded (FFPE) tissue or tissue obtained by a fresh biopsy
             for analyzing TP53 at a central laboratory.

        Exclusion Criteria:

        Medical Conditions

          1. Poor medical risk in the investigator's opinion because of systemic diseases in
             addition to the cancer under study, for example, uncontrolled infections.

          2. 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 ASTX295.

          3. History of, or at risk for, cardiac disease, as evidenced by any of the following
             conditions:

               1. Abnormal left ventricular ejection fraction.

               2. Congestive cardiac failure of ≥Grade 3.

               3. Unstable cardiac disease.

               4. History or evidence at Screening of long QT interval corrected for heart rate
                  (QTcF), ventricular arrhythmias, clinically significant bradyarrhythmias,
                  third-degree atrioventricular (AV) block, presence of cardiac pacemaker or
                  defibrillator, or other clinically significant arrhythmias.

               5. Screening 12-lead electrocardiogram (ECG) with measurable QTcF interval of ≥470
                  msec. (Fridericia's formula should be used).

          4. Known advanced human immunodeficiency virus (HIV) infection (including AIDS): clinical
             stage ≥ 3 according to WHO classification and/or HIV-associated immunodeficiency (CD4
             count less than 500 per mm3 of blood). Antiretroviral therapy (ART) is allowed
             (subjects should be on established ART for at least four weeks and have an HIV viral
             load less than 400 copies/mL prior to enrollment).

          5. Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (Inactive
             Hepatitis Carrier and subjects with laboratory evidence of no active replication on
             antivirals - viral load below limit of detection- will be permitted).

          6. Known brain metastases, unless previously treated and clinically stable for at least 4
             weeks with or without steroids.

          7. 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.

             Prior/Concomitant Therapy

          8. Prior anticancer treatments or therapies within the indicated time window prior to
             first dose of study treatment (ASTX295), as follows:

               1. Cytotoxic chemotherapy within 3 weeks prior. Any encountered treatment-related
                  toxicities (excepting alopecia) must be stabilized or resolved to ≤Grade 1.

               2. Monoclonal antibodies, biologics, or immunotherapy within 4 weeks prior. Any
                  encountered treatment-related toxicities must be stabilized or resolved to ≤Grade
                  1.

               3. 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 must be stabilized or resolved to ≤Grade 1.

               4. Major surgery or radiation within 4 weeks prior to first dose (palliative
                  radiotherapy to a single lesion within 2 weeks).

          9. Prior treatment with MDM2 antagonist

         10. Inability to swallow oral medication or inability or unwillingness to comply with the
             administration requirements related to ASTX295.

             Participants are excluded from the Phase 2 part of the study if any of the following
             additional criteria apply:

         11. Active malignancy other than the cancer under study (excludes low risk prostate
             cancer, basal cell carcinoma of the skin and superficial bladder cancer).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1a: To assess safety and tolerability of ASTX295 including determination of maximum tolerated dose (MTD), and/or recommended dose for expansion (RDE) to Phase 1b.
Time Frame:From the date of the first dose until 30 days after discontinuation of study treatment.
Safety Issue:
Description:The safety and tolerability will be based on Incidence and severity of treatment-emergent adverse events (AEs) including serious adverse events (SAEs) and dose limiting toxicities (DLTs)

Secondary Outcome Measures

Measure:Phase 1: To evaluate the preliminary clinical activity of ASTX295 as assessed by disease control rate (DCR).
Time Frame:From the date of the first dose until Week 16
Safety Issue:
Description:DCR will be calculated as the number of subjects whose response at Week 16 is CR, PR, or stable disease, divided by the total number of subjects evaluable for DCR analysis.
Measure:Phase 1: To evaluate the preliminary clinical activity as assessed by objective response rate (ORR) of ASTX295.
Time Frame:From the date of the first dose until study treatment discontinuation, an average of 6 months to 1 year.
Safety Issue:
Description:ORR will be calculated as the number of subjects whose best response is CR or PR, divided by the total number of subjects evaluable for ORR analysis.
Measure:Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (area under the curve [AUC]).
Time Frame:Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days).
Safety Issue:
Description:ASTX295 plasma concentration AUC
Measure:Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (minimum ocncentration [Cmin]).
Time Frame:Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days).
Safety Issue:
Description:ASTX295 plasma minimum concentration
Measure:Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (maximum concentration [Cmax]).
Time Frame:Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days).
Safety Issue:
Description:ASTX295 plasma maximum concentration
Measure:Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (time to reach maximum concentration [Tmax]).
Time Frame:Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days).
Safety Issue:
Description:The time to reach maximum concentration of ASTX295 in plasma.
Measure:Phase 1: To determine the pharmacokinetic (PK) profile of ASTX295 (elimination half-life [t½]).
Time Frame:Blood will be collected during Cycles 1 and 2 on Days 1 and 2 (each cycle is 28 days).
Safety Issue:
Description:The elimination half-life (t½) of ASTX295 in plasma.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Astex Pharmaceuticals

Trial Keywords

  • solid tumor
  • mesothelioma
  • TP53

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