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

NCT03224104 | Completed Phase 1 Results DMC

• 3 other identifiers: EORTC-1608-BTG2017-001029-42TG02-402
• Study Type: interventional
• Target: 71
• Locations: 5 countries
• Sites: 10

Brief Summary

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

Conditions

Astrocytoma, Grade III; Glioblastoma

Keywords

elderly; TG02; newly diagnosed; first relapse

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• Progression-free Survival

  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)

  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

  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

  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.

Study Arms (3)

Group A - TG02 + RT

EXPERIMENTAL

Elderly patients with IDH1R132H-non mutant and MGMT promoter-unmethylated anaplastic astrocytoma or glioblastoma who will receive TG02 and radiation therapy.

Drug: TG02; Radiation: Radiation Therapy

Group B - TG02 + TMZ

EXPERIMENTAL

Elderly patients with IDH1R132H-non mutant and MGMT promoter-methylated anaplastic astrocytoma or glioblastoma who will receive TG02 and temozolomide.

Drug: TG02; Drug: Temozolomide

Group C - TG02

EXPERIMENTAL

Patients initially diagnosed with anaplastic astrocytoma or glioblastoma at first relapse post TMZ/RT --\> TMZ therapy who will receive TG02.

Drug: TG02

Interventions

TG02 DRUG

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.

Group A - TG02 + RT; Group B - TG02 + TMZ; Group C - TG02

Radiation Therapy RADIATION

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

Group A - TG02 + RT

Temozolomide DRUG

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

Group B - TG02 + TMZ

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead
• Tragara Pharmaceuticals, Inc.: collaborator

Study Sites (10)

Universitaetskliniken der Uni Wien - Universitaetsklinikum Wien - AKH uniklinieken

Vienna, 1090, Austria

Location

CHU de Lyon - CHU Lyon - Hopital neurologique Pierre Wertheimer

Bron, 69677, France

Location

CHRU de Lille

Lille, France

Location

Assistance Publique - Hopitaux de Marseille - Hôpital de La Timone

Marseille, 13385, France

Location

Universitaetsklinikum Bonn

Bonn, 53205, Germany

Location

Klinikum Der J.W. Goethe Universitaet-Klinik und Poliklinik fur Neurochirurgie

Frankfurt, 60528, Germany

Location

Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital

Heidelberg, 69120, Germany

Location

Universitaetskliniken Regensburg - Universitaetsklinikum Regensburg

Regensburg, 93053, Germany

Location

Erasmus MC Cancer Institute - location Daniel den Hoed

Rotterdam, 3015, Netherlands

Location

UniversitaetsSpital Zurich

Zurich, 8091, Switzerland

Location

MeSH Terms

Conditions

Astrocytoma; Glioblastoma

Interventions

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; Radiotherapy; Temozolomide

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Therapeutics; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr Emilie Le Rhun
• Organization: UniversitaetsSpital Zurich - Neurology Clinic

emilie.lerhun@usz.ch

+41 762847518

Study Officials

• Emilie Le Rhun

  CHRU de Lille

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2017
• First Posted: July 21, 2017
• Study Start: June 12, 2018
• Primary Completion: May 5, 2022
• Study Completion: May 5, 2022
• Last Updated: November 26, 2025
• Results First Posted: November 26, 2025

Record last verified: 2025-11

Locations

CH (1); AU (1); FR (3); NL (1); DE (4)