- to determine the recommended phase 2 dose of TG02 in combination with radiotherapy in older patients (>65 years of age) with IDHwt glioblastoma and anaplastic astrocytoma without MGMT promoter methylation- to determine the recommended phase 2…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
group A: determination of the maximum tolerated dose of TGO2 in combination
with radiotherapy
group B: determination of the maximum tolerated dose of TGO2 in combination
with temozolomide
Groep C: progression free survival at 6 months
Secondary outcome
voor alle groups: landmark and median overall and progression free survival;
for group A and B quality of life, for group C neurological and clinical
deterioration free survival, response rate and duration, the adverse event
profile. Pharmacokinetics of TG02 (in group C only) at various timepoints
Background summary
The prognosis of patients with IDH wild type glioblastoma or anaplastic
astrocytoma is poor. The current treatment consists of combined
chemo-irradiation with temozolomide, but has a modest efficacy. Moreover, the
prognosis of elderly patients is in particular poor, and these patients are
more prone to side effects of treatment. The effectivity of the addition of
temozolomide to radiotherapy is depending on the MGMT promoter methylation
status. For those reasons, elderly patients with an unmethylated MGMT promoter
are often treated with radiotehrapy alone, and elderly patients with MGMT
promoter methylation are frequently treated with temozolomide monotherapy. Once
a IDHwt glioblastoma or anaplastic astrocytoma relapses, treatment options are
often limited to chemotherapy, with a limited response rate and duration. Thus,
this disease continues to represent an unmet clinical need and novel, effective
agents are urgently needed.
Abberations in Cyclin Dependand Kinases (CDK's) play a major role in many
malignancies. CDK inhibitors already registered for some malignancies,
including breast cancer. CDK's also play a role in glioblastoma. TGO2 is an
oral CDK9, 1, 2 5 and 7 inhibitor. CDK 5 is involved in the PI3K signalling
system, and in the migration of glioblastoma cells.
Study objective
- to determine the recommended phase 2 dose of TG02 in combination with
radiotherapy in older patients (>65 years of age) with IDHwt glioblastoma and
anaplastic astrocytoma without MGMT promoter methylation
- to determine the recommended phase 2 dose of TG02 in combination with
temozolomide in older patients (>65 years of age) with IDHwt glioblastoma and
anaplastic astrocytoma with MGMT promoter methylation
- to determine single agent activity of TG02 in patients with recurrent IDHwt
glioblastoma and anaplastic astrocytoma without MGMT promoter methylation to
determine if further stduies of this drug in this setting are justified
Study design
The study will be conducted in three groups of patients:
Group A: newly diagnosed older patients (>65 years of age) with IDHwt
glioblastoma and anaplastic astrocytoma without MGMT promoter methylation:
treatment with TG02 and radiotherapy 40 Gy in 15 fractions, starting dose TG02
100 mg twice weekly and escalation to 150 mg twice weekly or reduction based on
monitoring of toxicity
Grpoup B: newly diagnosed older patients (>65 years of age) with IDHwt
glioblastoma and anaplastic astrocytoma with MGMT promoter methylation:
treatment with TG02 and standard day 1-5 every 4 weeks temozolomide, starting
dose TG02 100 mg twice weekly and escalation to 150 mg twice weekly or
reduction based on monitoring of toxicity
Group C: patients with first recurrence of a IDHwt glioblastoma and anaplastic
astrocytoma after combined chemo-irradiation with temozolomide: treatment with
TG02 monotherapy 150 mg TGO2 twice weekly.
Intervention
group A: treatment with TGO2 and radiotherapye 40 gy in 15 fractions
group B: treatment with TGO2 and temozolomide standard dag 1-5 every 4 weeks
schedule
group C: treatment with TGO2 monotherapy
Study burden and risks
The patients are at risk to develop adverse events related to TGO2; and they
will undergo additional study measures such as quality of life questionnaires,
more frequent out patient clinic follow-up visits and more extensive drawing of
blood samples.
Av E Mounier 83/11
Brussel 1200
BE
Av E Mounier 83/11
Brussel 1200
BE
Listed location countries
Age
Inclusion criteria
Specifics for groups A and B , - Newly diagnosed glioblastoma or anaplastic
astrocytoma, IDH1R132H-nonmutant by immunohistochemistry locally assessed, with
FFPE tissue available for central MGMT testing (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
- Brain MRI within 14 days before the first dose of TG02
- central assessment of MGMT promoter methylation , Specifics for group C , -
IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse
with tissue available from first surgery
- 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 firstline
treatment
- 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.
- a post-surgery MRI made within 72 hours; , - For non-operated
patients: recurrent disease must be at least one bidimensionally 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
- Intention to be treated with standard RT/TMZ*-- >TMZ for initial treatment
and at least one dose of TMZ administered; RT alone or chemotherapy alone as
initial treatment are not permitted, 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
- Life expectancy > 8 weeks , - For men of reproductive potential and women of
childbearing potential: adequate contraception
- written informed consent
- Ability to take oral medication
Exclusion criteria
REGISTRATION , Specifics for groups A and B , * prior radiotherapy with overlap
of radiation fields with the planned radiotherapy in this study (Group A)
* prior therapy for glioblastoma or anaplastic astrocytoma before surgery ,
Specifics for group C , * discontinuation of TMZ for toxicity during first-line
treatment
* no other treatment except surgery for the treatment of the first recurrence ,
All groups
* use of enzyme-inducing anti-epileptic drugs (EI-AED) within 7 days prior to
the first dose of TG02 ,
* history of ventricular arrhythmia or symptomatic conduction abnormality in
past 12 months prior to registration
* congestive heart failure (New York Heart Association Class III to IV,
symptomatic ischemia, uncontrolled by conventional intervention, or myocardial
infarction within 6 months prior to enrollment
* prolonged QTc interval (males: > 450 ms; females: > 470 ms)
* known contraindication to imaging tracer or any product of contrast media
* MRI contraindications , * concurrent severe or uncontrolled medical disease
, * known human immunodeficiency virus infection or acquired immune deficiency
syndrome , * previous other malignancies, except for any previous malignancy
which was treated with curative intent more than 3 years prior to enrollment,
and except for adequately controlled limited basal cell carcinoma of the skin,
squamous carcinoma of the skin or carcinoma in situ of the cervix , * Negative
serum or urine pregnancy test within 72 hours prior to the first dose for
WOCBP. Nursing must be discontinued at least 1 hour before first dose.
* Known hypersensitivity to the active substance of any of the excipients in
the TG02 formulation, dacabarzine and temozolomide, * Any psychological,
familial, sociological or geographical condition potentially hampering
compliance with the study protocol and follow-up schedule
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001029-42-NL |
| ClinicalTrials.gov | NCT03224104 |
| CCMO | NL64274.078.18 |