Multi-kinase Inhibitor TG02 (TG02) in Elderly Newly Diagnosed or Adult Relapsed Patients With Anaplastic Astrocytoma or Glioblastoma. (STEAM)

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

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

Study Overview

• Status: Completed
• Conditions: Glioblastoma; Astrocytoma, Grade III
• Intervention / Treatment: Drug: TG02; Radiation: Radiation Therapy; Drug: Temozolomide

Detailed Description

Group A will be composed of newly-diagnosed, elderly patients with Isocitrate dehydrogenase 1 (IDH1) gene non mutant (IDH1R132H) and O-6-methylguanine-DNA methyltransferase (MGMT) promoter-unmethylated anaplastic astrocytoma or glioblastoma who will receive TG02 and radiotherapy (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
• Enrollment (Actual): 71
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Universitaetskliniken der Uni Wien - Universitaetsklinikum Wien - AKH uniklinieken
• France
  • Bron, France, 69677
    • CHU de Lyon - CHU Lyon - Hopital neurologique Pierre Wertheimer
  • Lille, France
    • CHRU de Lille
  • Marseille, France, 13385
    • Assistance Publique - Hopitaux de Marseille - Hôpital de La Timone
• Germany
  • Bonn, Germany, 53205
    • Universitaetsklinikum Bonn
  • Frankfurt, Germany, 60528
    • Klinikum Der J.W. Goethe Universitaet-Klinik und Poliklinik fur Neurochirurgie
  • Heidelberg, Germany, 69120
    • Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital
  • Regensburg, Germany, 93053
    • Universitaetskliniken Regensburg - Universitaetsklinikum Regensburg
• Netherlands
  • Rotterdam, Netherlands, 3015
    • Erasmus MC Cancer Institute - location Daniel den Hoed
• Switzerland
  • Zurich, Switzerland, 8091
    • UniversitaetsSpital Zurich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Specifics for groups A and B

• Newly diagnosed glioblastoma or anaplastic astrocytoma, IDH1R132H-non-mutant by immunohistochemistry locally assessed, with formalin-fixed, paraffin-embedded (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 World Health Organization (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 isocitrate dehydrogenase 2 (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:
• white blood cell (WBC) ≥ 3 x109/L
• absolute neutrophil count (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 × upper limit of normal (ULN)
• Alanine transaminase (ALT) and aspartate aminotransferase (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 corrected QT interval (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 International Conference on Harmonization ICH) / Good Clinical Practice (GCP), and national/local regulations.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	The primary objective in Groups A and B of the EORTC-1608 study is to establish the Maximum Tolerated Dose (MTD) of TG02 and the recommended phase II dose when combined with either radiotherapy (Group A) or temozolomide (Group B) for glioblastoma treatment. The MTD is the highest dose where no more than one of six patients experiences a Dose Limiting Toxicity (DLT). The study requires a 75% dose intensity for TG02 and the concurrent treatment. The trial uses a two-cohort design to assess TG02 with hypofractionated radiotherapy in patients with an unmethylated MGMT promoter or with temozolomide in those with a methylated promoter. Dose escalation begins at 100 mg TG02 twice weekly. If no DLTs occur in the first three patients, the dose increases to 150 mg. If one patient has a DLT, three more are enrolled at the same dose. If no further DLTs occur, escalation continues. If more than one patient has a DLT, escalation stops, and the previous dose is the MTD.	From the initiation of TG02 treatment until the determination of the Maximum Tolerated Dose (MTD) for each participant, which is expected to occur within the first 28-day cycle for most participants.
Percentage of Participants Maintaining Progression-free Survival at 6 Months (PFS-6)	The primary endpoint for Group C is Progression-free survival at 6 months (PFS-6), assessed by Response Assessment in Neuro-Oncology (RANO) criteria. Complete Response (CR) is defined as the disappearance of all enhancing measurable and nonmeasurable disease for at least 4 weeks. Partial Response (PR) requires at least a 50% decrease in the sum of products of perpendicular diameters of all measurable enhancing lesions for at least 4 weeks. Stable Disease (SD) is when the patient does not qualify for CR, PR, or progression, with stable nonenhancing lesions on the same or lower dose of corticosteroids. Progression (PD) is defined as at least a 25% increase in the sum of products of perpendicular diameters of enhancing lesions compared to the smallest measurement at baseline or best response, a significant increase in T2/FLAIR lesion, any new lesion, or clear clinical deterioration not attributable to other causes.	The time frame for assessing PFS spans from the date of consent to either disease progression or death. Data are specifically presented for the 6-month time point.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression-free survival (PFS) is a secondary endpoint for Group C. PFS is defined as the number of days from consent to the date of earliest disease progression based on Response Assessment in Neuro Oncology (RANO) criteria (as determined by the Investigator) or to the date of death, if disease progression does not occur. For all groups, the median PFS will be determined. PFS is measured from the start of treatment until the date of disease progression or death, whichever occurs first. Patients without progression or death will be censored at the last date documented to be alive and progression-free.	The time frame for assessing PFS is the duration from the date of consent until disease progression or death. PFS was assessed by its median the point time at which 50% of the patients have experienced death.
Overall Survival (OS)	Overall Survival (OS) is a secondary endpoint for Group C. OS is defined as the number of days from consent to the date of death due to any cause. If a patient has not died, the data was censored at the last date documented to be alive. For all groups, the median OS was determined. The median OS was extracted from the Kaplan-Meier OS curve,	The time frame for assessing OS is from consent to the date until death or the end of the study, whichever comes first. OS was assessed by its median the point time at which 50% of the patients have experienced death.
Objective Response	Objective Response (OR) is a secondary endpoint for Group C. For patients with measurable disease after debulking or non-surgical patients with measurable disease after surgery for recurrence, the best overall response distribution (BOR), objective response rate (PR+CR), complete response rate, and duration of response (DOR) was assessed. The objective response rate is the proportion of patients who achieve a partial response (PR) or complete response (CR), while the complete response rate is the proportion of patients who achieve a CR. The duration of response (DOR) is the time from the first documented response (PR or CR) to the date of disease progression or death, whichever occurs first.	Time frame for assessing response is from the initiation of treatment with TG02 until disease progression or death. It was not assessed at specific time point but throughout the study. The OR rate is determined based on the best response observed.
Neurological Progression-free Survival	Neurological progression-free survival (NPFS) is a secondary endpoint for Group C. NPFS is defined based on the Neurologic Assessment in Neuro-Oncology (NANO) criteria. NPFS is measured from the date of enrollment in the trial until the date of first neurological progression or death, whichever occurs first. If a patient does not experience neurological progression or death, the data will be censored at the last date of post-baseline neurological assessment. The median NPFS will be determined.	The time frame for assessing NPFS spans from the date of consent to either disease progression or death.NPFS was assessed by its median the point time at which 50% of the patients have experienced death.

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Tragara Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Emilie Le Rhun, CHRU de Lille

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2018
• Primary Completion (Actual): May 5, 2022
• Study Completion (Actual): May 5, 2022

Study Registration Dates

• First Submitted: July 6, 2017
• First Submitted That Met QC Criteria: July 17, 2017
• First Posted (Actual): July 21, 2017

Study Record Updates

• Last Update Posted (Actual): November 26, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: elderly; newly diagnosed; TG02; first relapse
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Astrocytoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Azoles; Dacarbazine; Triazenes; Imidazoles; Temozolomide; Radiotherapy; 14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene
• Other Study ID Numbers: EORTC-1608-BTG; 2017-001029-42 (EudraCT Number); TG02-402 (Other Identifier: Tragara Pharmaceuticals, Inc.)

Drug and device information, study documents

• 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