Clinical Trials /

Study of TG02 in Elderly Newly Diagnosed or Adult Relapsed Patients With Anaplastic Astrocytoma or Glioblastoma

NCT03224104

Description:

This is a three parallel cohort, open-labeled, non-randomized, multicenter study. All three cohorts will enroll independently.

Related Conditions:
  • Anaplastic Astrocytoma
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of TG02 in Elderly Newly Diagnosed or Adult Relapsed Patients With Anaplastic Astrocytoma or Glioblastoma
  • Official Title: Study of TG02 in Elderly Newly Diagnosed or Adult Relapsed Patients With Anaplastic Astrocytoma or Glioblastoma: A Phase Ib Study

Clinical Trial IDs

  • ORG STUDY ID: EORTC-1608-BTG
  • SECONDARY ID: 2017-001029-42
  • SECONDARY ID: TG02-402
  • NCT ID: NCT03224104

Conditions

  • Astrocytoma, Grade III
  • Glioblastoma

Interventions

DrugSynonymsArms
TG02Group A - TG02 + RT
TemozolomideGroup B - TG02 + TMZ

Purpose

This is a three parallel cohort, open-labeled, non-randomized, multicenter study. All three cohorts will enroll independently.

Detailed Description

      Group A will be composed of newly-diagnosed, elderly patients with IDH1R132H-non mutant and
      MGMT promoter-unmethylated anaplastic astrocytoma or glioblastoma who will receive TG02 and
      RT.

      Group B will be composed of newly-diagnosed, elderly patients with IDH1R132H-non mutant and
      MGMT promoter-methylated anaplastic astrocytoma or glioblastoma who will receive TG02 and
      temozolomide.

      For both Groups A and B, there will be a classical 3+3 dose escalation and an expansion phase
      in the study. Up to a total of 24 evaluable patients in Group A and up to a total of 12
      evaluable patients in Group B (up to 36 evaluable patients for Groups A and B).

      Group C patients will be composed of patients initially diagnosed with IDH1R132H-non-mutant
      anaplastic astrocytoma or glioblastoma at first relapse post TMZ/RT-->TMZ therapy who will
      receive TG02.
    

Trial Arms

NameTypeDescriptionInterventions
Group A - TG02 + RTExperimentalElderly patients with IDH1R132H-non mutant and MGMT promoter-unmethylated anaplastic astrocytoma or glioblastoma who will receive TG02 and radiation therapy.
  • TG02
Group B - TG02 + TMZExperimentalElderly patients with IDH1R132H-non mutant and MGMT promoter-methylated anaplastic astrocytoma or glioblastoma who will receive TG02 and temozolomide.
  • TG02
  • Temozolomide
Group C - TG02ExperimentalPatients initially diagnosed with anaplastic astrocytoma or glioblastoma at first relapse post TMZ/RT --> TMZ therapy who will receive TG02.
  • TG02

Eligibility Criteria

        Specifics for groups A and B

          -  Newly diagnosed glioblastoma or anaplastic astrocytoma, IDH1R132H-non-mutant by
             immunohistochemistry locally assessed, with FFPE tissue available for central MGMT
             testing and optional biomarker studies (treatment allocation will be performed based
             on centrally assessed MGMT result)

          -  Tumor debulking surgery, including partial resection

          -  Age > 65 and considered non-eligible for combination therapy (TMZ/RT→TMZ) in
             Investigator's opinion

          -  No prior RT with overlap of radiation fields with the planned RT in this study (Group
             A)

          -  No prior therapy for glioblastoma or anaplastic astrocytoma before surgery

          -  Brain MRI within 14 days before the first dose of TG02

        Specifics for group C

          -  IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse with
             tissue available from first surgery. [Per 2016 WHO classification, in patients older
             than 55 years of age at diagnosis with a histological diagnosis of glioblastoma,
             without a pre-existing lower grade glioma and with non-midline tumor location,
             immunohistochemical negativity for IDH1R132H suffices for classification as
             glioblastoma. In all other instances of diffuse gliomas, lack of IDH1R132H
             immunopositivity should be followed by IDH1 and IDH2 sequencing to detect or exclude
             other less common IDH mutations.]

          -  Brain MRI at the time of progression or 14 days before the first dose of TG02 and
             availability of last brain MRI before progression diagnosis for upload to the EORTC
             Imaging Platform for post-hoc central review of progression

          -  Diagnosis of recurrence more than 3 months after the end of RT for initial treatment

          -  Intention to be treated with standard TMZ/RT→TMZ for initial treatment (at least one
             dose of TMZ administered; RT alone or chemotherapy alone as initial treatment are not
             permitted)

          -  No discontinuation of TMZ for toxicity during first-line treatment

          -  No RT or stereotactic radiosurgery is allowed for the treatment of first recurrence
             prior to enrollment in this study

          -  Patient may have been operated for recurrence. If operated:

          -  surgery completed at least 2 weeks before initiation of TG02 and patients should have
             fully recovered as assessed by investigator. Criteria for full recovery include
             absence of active post-operative infection, recovery from medical complications (CTCAE
             grade 0 and 1 acceptable), and capacity for adequate fluid and food intake

          -  residual and measurable disease after surgery is not required but surgery must have
             confirmed the recurrence

          -  a post-surgery MRI should be available within 72 hours; the post-surgery MRI can be
             used as baseline if performed within 2 weeks prior to registration. If not, a baseline
             MRI has to be done within 2 weeks prior to registration

          -  For non-operated patients: recurrent disease must be at least one bi-dimensionally
             measurable contrast-enhancing lesion with clearly defined margins by MRI scan, with
             minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on a
             MRI scan done within 2 weeks prior to registration

          -  Age ≥ 18 years

        All groups

          -  Karnofsky Performance Score (KPS) of 60-100

          -  Recovered from effects of debulking surgery, postoperative infection and other
             complications of surgery (if any) (CTCAE grade 0 and 1 acceptable)

          -  Adequate bone marrow, renal and hepatic function within the following ranges within 7
             days before the first dose of TG02:

          -  WBC ≥ 3 x109/L

          -  ANC ≥ 1.5x109/L

          -  Platelet count of ≥ 100 x109/L independent of transfusion

          -  Hemoglobin ≥ 10 g/dl or ≥ 6.2 mmol/L

          -  Bilirubin ≤ 1.5 × ULN

          -  ALT and AST ≤ 2.5 × ULN

          -  Cockcroft-Gault calculated or measured creatinine clearance of ≥ 30 mL/min

          -  No use of enzyme-inducing anti-epileptic drugs (EI-AED) within 7 days prior to the
             first dose of TG02

          -  Life expectancy > 8 weeks

          -  No history of ventricular arrhythmia or symptomatic conduction abnormality in past 12
             months prior to registration

          -  No congestive heart failure (New York Heart Association Class III to IV, see Appendix
             C), symptomatic ischemia, uncontrolled by conventional intervention, or myocardial
             infarction within 6 months prior to enrollment

          -  No 12-lead ECG with a prolonged QTc interval (males: > 450 ms; females: > 470 ms) as
             calculated by the Fridericia correction formula despite balancing of electrolytes at
             registration and/or discontinuing any drugs (for a time period corresponding to 5
             half-lives) known to prolong QTc interval

          -  No known contraindication to imaging tracer or any product of contrast media

          -  No MRI contraindications

          -  No concurrent severe or uncontrolled medical disease (e.g., active systemic infection,
             diabetes, hypertension, coronary artery disease) that, in the opinion of the
             Investigator, would compromise the safety of the patient or compromise the ability of
             the patient to complete the study

          -  No known human immunodeficiency virus infection or acquired immune deficiency syndrome

          -  No previous other malignancies, except for any previous malignancy which was treated
             with curative intent more than 3 years prior to enrollment, or adequately controlled
             limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma
             in situ of the cervix

          -  No pregnant women. Negative serum or urine pregnancy test within 72 hours prior to the
             first dose for women of childbearing potential (WOCBP). Nursing must be discontinued
             at least 1 hour before first dose.

          -  For men of reproductive potential and WOCBP, adequate contraception must be used
             throughout the study and for 6 months thereafter. For this study, acceptable methods
             of contraception include a reliable intrauterine device or a spermicide in combination
             with a barrier method. Hormonal forms of birth control (oral, implantable, or
             injectable) may only be used if combined with another highly effective form of birth
             control such as a spermicide combined with a barrier method

          -  Ability to understand the requirements of the study, provide written informed consent
             and authorization of use and disclosure of protected health information, and agree to
             abide by the study restrictions and return for the required assessments

          -  Ability to take oral medication

          -  Absence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule; those
             conditions should be discussed with the patient before registration in the trial

          -  Before patient registration, written informed consent must be given according to
             ICH/GCP, and national/local regulations.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:27 months from first patient in
Safety Issue:
Description:Primary endpoints in Groups A and B are the determination of the Maximum Tolerated Dose (MTD) and the recommended phase II combination dose. This part is a two-cohort study of the combination of TG02 with hypofractionated RT in patients with tumors with an unmethylated MGMT promoter, or with TMZ in patients with tumors with a methylated MGMT promoter. Up to two dose levels of TG02 will be explored in each group.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:30 months from first patient in
Safety Issue:
Description:Progression-free survival (PFS) defined by RANO criteria. For groups A and B progression-free survival at 6 months (PFS-6), for group all groups median progression-free survival.
Measure:Overall survival (OS)
Time Frame:30 months from first patient in
Safety Issue:
Description:For all groups median overall survival and OS at 9 months (OS-9), for group C additional overall survival at 1 year (OS-12).
Measure:Response to treatment
Time Frame:30 months from first patient in
Safety Issue:
Description:For patients with measurable disease after debulking: best overall response distribution (BOR), objective response rate (PR+CR), complete response rate and duration of response (DOR). For non-surgical patients or patients with surgery for recurrence, but measurable disease thereafter: best overall response distribution (BOR), objective (PR+CR) rate, complete response rate and duration of response (DOR)
Measure:Neurological progression-free survival
Time Frame:30 months from first patient in
Safety Issue:
Description:For group C: neurological progression-free survival (NPFS) based on the Neurologic Assessment in Neuro-Oncology (NANO): median NPFS and NPFS at 6 months (NPFS-6).
Measure:Toxicity according CTCAE version 4.0
Time Frame:30 months from first patient in
Safety Issue:
Description:This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.
Measure:Molecular markers
Time Frame:30 months from first patient in
Safety Issue:
Description:Correlation of molecular markers including MYC, MCL-1, CDK9 and CDK5 protein levels, and potentially others, with measures of clinical benefit.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

Trial Keywords

  • elderly
  • TG02
  • newly diagnosed
  • first relapse

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