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

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ClinicalTrials.gov Identifier: NCT03224104
Recruitment Status : Recruiting
First Posted : July 21, 2017
Last Update Posted : June 8, 2018
Sponsor:
Collaborator:
Tragara Pharmaceuticals, Inc.
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

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

Condition or disease Intervention/treatment Phase
Astrocytoma, Grade III Glioblastoma Drug: TG02 Radiation: Radiation Therapy Drug: Temozolomide Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of TG02 in Elderly Newly Diagnosed or Adult Relapsed Patients With Anaplastic Astrocytoma or Glioblastoma: A Phase Ib Study
Estimated Study Start Date : June 2018
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020


Arm Intervention/treatment
Experimental: Group A - TG02 + RT
Elderly patients with IDH1R132H-non mutant and MGMT promoter-unmethylated anaplastic astrocytoma or glioblastoma who will receive TG02 and radiation therapy.
Drug: TG02

The initial cohorts of Groups A and B will receive TG02 at 200 mg on intermittent schedules in combination with either RT or TMZ. TG02 will be escalated to 250 mg if the dose decision criteria are met in the first cohort.

The initial cohort in Group C will receive TG02 alone at 250 mg on intermittent schedules. It will be continued at this dose if feasible or decreased to 200 or 150 mg if not tolerated.


Radiation: Radiation Therapy
For group A standard involved-field hypofractionated RT will be administered at 39.9 Gy in 15 fractions of 2.66 Gy for 3 weeks

Experimental: Group B - TG02 + TMZ
Elderly patients with IDH1R132H-non mutant and MGMT promoter-methylated anaplastic astrocytoma or glioblastoma who will receive TG02 and temozolomide.
Drug: TG02

The initial cohorts of Groups A and B will receive TG02 at 200 mg on intermittent schedules in combination with either RT or TMZ. TG02 will be escalated to 250 mg if the dose decision criteria are met in the first cohort.

The initial cohort in Group C will receive TG02 alone at 250 mg on intermittent schedules. It will be continued at this dose if feasible or decreased to 200 or 150 mg if not tolerated.


Drug: Temozolomide
For group B TMZ will be given in the standard 28-day cycle regimen (150-200 mg/m2) for 5 days.

Experimental: Group C - TG02
Patients initially diagnosed with anaplastic astrocytoma or glioblastoma at first relapse post TMZ/RT --> TMZ therapy who will receive TG02.
Drug: TG02

The initial cohorts of Groups A and B will receive TG02 at 200 mg on intermittent schedules in combination with either RT or TMZ. TG02 will be escalated to 250 mg if the dose decision criteria are met in the first cohort.

The initial cohort in Group C will receive TG02 alone at 250 mg on intermittent schedules. It will be continued at this dose if feasible or decreased to 200 or 150 mg if not tolerated.





Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: 27 months from first patient in ]
    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.

  2. Progression-free survival at 6 months (PFS-6) [ Time Frame: 30 months from first patient in ]
    Primary endpoint in Group C is Progression-free survival at 6 months (PFS-6) defined by RANO criteria.


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 30 months from first patient in ]
    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.

  2. Overall survival (OS) [ Time Frame: 30 months from first patient in ]
    For all groups median overall survival and OS at 9 months (OS-9), for group C additional overall survival at 1 year (OS-12).

  3. Response to treatment [ Time Frame: 30 months from first patient in ]

    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)


  4. Neurological progression-free survival [ Time Frame: 30 months from first patient in ]
    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).

  5. Toxicity according CTCAE version 4.0 [ Time Frame: 30 months from first patient in ]
    This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.

  6. Molecular markers [ Time Frame: 30 months from first patient in ]
    Correlation of molecular markers including MYC, MCL-1, CDK9 and CDK5 protein levels, and potentially others, with measures of clinical benefit.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03224104


Contacts
Contact: Tina Verschuere +32 2 774 1504 1608@eortc.org

Locations
France
CHRU de Lille Recruiting
Lille, France
Contact: Emilie Le Rhun       emilie.lerhun@chru-lille.fr   
Switzerland
UniversitaetsSpital Zurich Recruiting
Zürich, Switzerland, 8091
Principal Investigator: Michael Weller         
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Tragara Pharmaceuticals, Inc.
Investigators
Principal Investigator: Emilie Le Rhun CHRU de Lille

Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT03224104     History of Changes
Other Study ID Numbers: EORTC-1608-BTG
2017-001029-42 ( EudraCT Number )
TG02-402 ( Other Identifier: Tragara Pharmaceuticals, Inc. )
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: June 8, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
elderly
TG02
newly diagnosed
first relapse

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents