Phase III randomised trial evaluating chemotherapy early treatment intensification with temozolomide in adults present with a glioblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Oscar Lambret

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02]

Trial duration

18 Mar 2019 → ongoing

Decision date (initial)

2025-11-10

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2022-500451-23-00

EudraCT number

2018-000410-38

ClinicalTrials.gov

NCT03663725

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To evaluate the impact of intensification with early Temozolomide ) compared to Stupp standard protocol, in terms of Overall Survival (OS)

Secondary objectives 7

1. To compare safety (hematological and non hematological adverse events) between both arms (intensified protocol vs standard protocol)
2. To evaluate the efficacy of intensification in terms of progression-free survival (PFS)
3. To evaluate the relative benefit/risk ratio using the Q-TWiST approach
4. Exploratory objectives : To evaluate the feasibility of intensified treatment by comparing it to that of the standard treatment, in terms of doses received and dose-intensity
5. To identify prognostic factors of OS and predictive factors of treatment response (clinical and biological factors, including MGMT methylation).
6. To describe the type of the progression (local or peri-local, remote in the brain, remote in the meninges)
7. To describe post-progression treatments

Conditions and MedDRA coding

Adults with a de novo glioblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Patient ≥18 years old
2. Histological diagnosis of de novo GBM (extemporaneous diagnosis or standard pathological examination). In case of extemporaneous diagnosis, the patient can be included. If the diagnosis is not confirmed, the patient will be withdrawn from study.
3. Time between initial surgery/biopsy and planned start of treatment (if allocated to the experimental arm) ≤ 14 days (ideally in the first 7 days)
4. Karnofsky performance status (KPS) ≥ 60%, or KPS <60% only related to glioma-related motor paresis.
5. Adequate biological functions: neutrophils ≥ 1500/mm3, platelets ≥ 100 000/mm3 independent of transfusion, serum creatinine ≤ 1.5 times ULN; transaminases (ALAT/ ASAT) ≤ 3 times ULN; total bilirubin ≤ 1.5 times ULN (except in case of Gilbert’s disease)
6. Common toxicity criteria (CTC) non hematological adverse events ≤ Grade 1 (except for alopecia, nausea, vomiting and neurological symptoms)
7. Females of child bearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active patients must agree to use adequate and appropriate contraception while on study drug and for 6 months after stopping the study drug.
8. Standard radiation therapy deemed feasible (60 Gy, 30 fractions)
9. Time interval of less than 43 days between initial surgery/biopsy and planned start of radiation therapy
10. planned MGMT analysis (results not mandatory at inclusion but must be further reported in the eCRF)
11. Written informed consent from patient or the person of trust (“personne de confiance”)
12. France and Belgium: Patient covered by the French or Belgian “Social Security” regime

Exclusion criteria 11

1. IDH-mutant (IDH1 ou IDH2) astrocytoma (grade 4) or recurrent gliosblastoma (GBM)
2. Planned use of Carmustine implants
3. Prior malignancy in the last 5 years before inclusion or concomitant
4. Severe myelosuppression
5. Known hypersensitivity to any of the study drugs, study drug classes, excipients in the formulation or to dacarbazine (DTIC)
6. Current or recent treatment with another experimental drug or patients included in a clinical therapeutic trial (in the 30 days prior to inclusion)
7. Known current viral hepatitis, HIV infection or current active infectious disease
8. Inability to swallow oral medications or any mal-absorption condition
9. Pregnant or breastfeeding patients.
10. Inability to comply with medical follow-up of the trial (geographical, social or psychological reasons)
11. Person under guardianship or curatorship

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival will be defined as time interval from randomization to death whatever the cause. Patients alive will be censored at the date of last news.

Secondary endpoints 7

1. Adverse events occurring from randomization until disease progression will be reported and graded using the NCI-CTCAE v5.0 classification, including those related to the underlying disease or its progression. All AE will be analyzed, and described according to the reported causal relationship. An AE will be classified as Severe AE if grade is equal or higher than 3 for extra-hematological AE and grade 4 for hematological AE.
2. Progression-free survival will be defined as time interval from randomization to the first occurrence of progression according to RANO criteria as assessed by the treating physician, or death whatever the cause. Patients alive without progressive disease will be censored at the date of last news. There will be no central radiological review. The type of progression will be collected (local or peri-local, remotely in the brain, remotely in the meninges)
3. Q-TWiST: Quality-adjusted time without symptoms of disease or adverse event
4. Exploratory endpoints: Treatment doses will be computed for each treatment component (radiotherapy & chemotherapy), and by treatment phase (early TMZ / concomitant TMZ / adjuvant TMZ). Early administration of TMZ is unlikely to result in leucopenia and/or thrombocytopenia, which could prevent or inhibit conventional concomitant standard dose chemoradiotherapy. It could also lead to platelet transfusions or infections. Patients will be notified. The percentage of deliveries of complete chemoradio
5. Total dose of irradiation received and dose-intensity.
6. Predictive factors of overall survival: the list of studied factors will be defined later. The methylation of the MGMT promoter is mandatory and will be done in each center. Tumor material will be stored in order to study other biomarkers.
7. Description of the post-progression treatments: nature and duration.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Oscar Lambret

Sponsor organisation

Centre Oscar Lambret

Address

3 Rue Frederic Combemale

City

Lille

Postcode

59000

Country

France

Scientific contact point

Organisation

Centre Oscar Lambret

Contact name

Clinical Research Sponsor Unit

Public contact point

Organisation

Centre Oscar Lambret

Contact name

Clinical Research Sponsor Unit

Locations

2 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications