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

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

Detailed Description
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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.

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

Conditions
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Astrocytoma, Grade III, Glioblastoma

Intervention / Treatment
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* Drug: TG02
* Radiation: Radiation Therapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A - TG02 + RT<br>Elderly patients with IDH1R132H-non mutant and MGMT promoter-unmethylated anaplastic astrocytoma or glioblastoma who will receive TG02 and radiation therapy. | Drug: TG02<br>* 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.<br>Radiation: Radiation Therapy<br>* 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<br>|
| Experimental: Group B - TG02 + TMZ<br>Elderly patients with IDH1R132H-non mutant and MGMT promoter-methylated anaplastic astrocytoma or glioblastoma who will receive TG02 and temozolomide. | Drug: TG02<br>* 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.<br>Drug: Temozolomide<br>* For group B TMZ will be given in the standard 28-day cycle regimen (150-200 mg/m2) for 5 days.<br>|
| Experimental: Group C - TG02<br>Patients initially diagnosed with anaplastic astrocytoma or glioblastoma at first relapse post TMZ/RT --> TMZ therapy who will receive TG02. | Drug: TG02<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | 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. | 27 months from first patient in | 
| Progression-free survival at 6 months (PFS-6) | Primary endpoint in Group C is Progression-free survival at 6 months (PFS-6) defined by RANO criteria. | 30 months from first patient in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | 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. | 30 months from first patient in | 
| Overall survival (OS) | For all groups median overall survival and OS at 9 months (OS-9), for group C additional overall survival at 1 year (OS-12). | 30 months from first patient in | 
| Response to treatment | 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) | 30 months from first patient in | 
| Neurological progression-free survival | 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). | 30 months from first patient in | 
| Toxicity according CTCAE version 4.0 | This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting. | 30 months from first patient in | 
| Molecular markers | Correlation of molecular markers including MYC, MCL-1, CDK9 and CDK5 protein levels, and potentially others, with measures of clinical benefit. | 30 months from first patient in | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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elderly, TG02, newly diagnosed, first relapse