Phase III trial of lomustine/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMT promoter methylated glioblastoma (IDHwt) patients +/- tumor treating fields (Optune)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vaestra Goetalandsregionen, Region Oestergoetland

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Nervous System Diseases [C10]

Trial duration

8 Jan 2025 → ongoing

Decision date (initial)

2025-06-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective of this phase III trial is to determine whether combined TMZ/LOM chemotherapy plus standard radiotherapy +/- concomitant TTFields is superior regarding overall survival, to TMZ monochemotherapy plus standard radiotherapy +/-concomitant TTFields in patients with newly diagnosed mMGMT GBM tumor. That is, if the addition of LOM to primary treatment for mMGMT GBM leads to a significant survival benefit when added to standard treatment which may or may not include TTFields.

Secondary objectives 4

1. The secondary objectives of this trial are to determine whether combined TMZ/LOM chemotherapy plus standard radiotherapy +/-concomitant TTFields is superior regarding progression-free survival as well as to determine acute and late toxicity of TMZ/LOM therapy +/-concomitant TTFields including its side-effects such as the delay of subsequent cycles due to acute toxicity, compared to TMZ monotherapy +/- concomitant TTFields.
2. secondary objectives include best response rate determined by MRI, time to treatment failure (both progression and toxicity), frequency of pseudoprogression, location of tumor recurrences. Quality of life and neurocognitive evaluation will be performed, and also related to radiotherapy dose in hippocampus and normal brain. Assessment of treatment related neurotoxicity on MRI will also be conducted. The role of baseline comorbidities in relation to OS will be investigated.
3. Potential differences in survival, QoL and neurocognition between patients receiving TTFields or not will be looked at.
4. Tumor tissue from the primary surgery will be investigated for basic diagnostic and translational research. Blood for liquid biopsies is planned to be analyzed for “Tumor Educated Platelets”, circulating free tumor DNA and exosomes.

Conditions and MedDRA coding

Glioblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Written informed consent
2. Patient capable of understanding the rationale and necessity of study therapy and procedures.
3. Newly diagnosed histologically proven GBM, giant-cell GBM or gliosarcoma WHO Grad 4, histology confirmed by the local neuropathologist as IDHwt. Histology obtained by complete resection, partial resection, open biopsy or stereotactic biopsy.
4. Methylated MGMT promoter in the tumor as determined according to local routine. For centers using the same method/kit the same cut-off for mMGMT will be used.
5. Males or females 18-75 years of age, estimated life expectancy of at least 12 weeks
6. WHO Performance Score 0-2
7. Patient compliance and geographic proximity that allow adequate follow up
8. Male and female patients with reproductive potential must use an approved contraceptive method (intrauterine device, birth control pills, or barrier device) during and for 6 months after end of chemotherapy (Pearl index <1%)
9. Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test must be obtained within 14 days prior to treatment start
10. Adequate organ function as described in the protocol
11. Patients on anticoagulation can be included at the discretion of the investigator, but oral anticoagulants, including NOAC/DOAC are recommended to be switched to Low-molecular-weight heparin (LMWH) during the treatment phase and until platelets are >50 or according to local guidelines.

Exclusion criteria 14

1. Prior malignancy (except adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer), unless the prior malignancy was diagnosed and curatively treated ≥3 years previously with no subsquent evidence of recurrence
2. Prior systemic chemotherapy with DNA-damaging agents for any cancer
3. Prior RT to the brain
4. Concurrent administration of any other antitumor therapy not described in the protocol
5. Concurrent administration of complementary or alternative drugs
6. Allergy or intolerability of temozolomide, dacarbazine, lomustine or other nitrosourea derivatives including celiac disease and wheat allergy
7. Unable to perform MRI
8. Past medical history of diseases with poor prognosis, e.g. severe coronary heart disease, heart failure (NYHA III/IV), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
9. Severly reduced lung function (at the discretion of the investigator)
10. Any active infection (at the discretion of the investigator)
11. Female patients that are breastfeeding and not willing to refrain
12. Patients with reproductive potential who do not accept to use contraception during chemotherapy and 6 months thereafter
13. Treatment in another clinical trial with oncological therapeutic intervention or use of any other investigational agent within 30 days before enrolment
14. Any psychological, cognitive, familial, social or geographical condition potentially hampering compliance with the study protocol and follow-up scheduled visits (at the discretion of investigator)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS) as measured from the day of randomisation until death or follow-up of at least 36 months.

Secondary endpoints 14

1. Progression-free survival (PFS) as measured from the day of randomisation until diagnosis of progressive disease determined by MRI (RANO 2.0 criteria)
2. Best response rate determined by MRI (RANO 2.0 criteria)
3. Frequency of delay of the next TMZ/LOM or TMZ cycle by more than 2 weeks
4. Acute toxicity during radiotherapy and chemotherapy +/- TTFields according to CTCAE latest available version at study start
5. Quality of life, determined by EORTC questionnaires QLQ-30 and BN-20
6. Evaluation of neurocognition determined by CNS Vital Signs
7. Frequency of pseudoprogression
8. Location of tumor recurrence in relation to radiotherapy isodose curves
9. Dose to hippocampus and healthy brain in relation to QoL and neurocognitive testing
10. Analysis of OS and PFS for the subgroup of patients receiving TTFields in relation to those not receiving TTFields per treatment arm and combined for both treatment arms (all TTFields patients versus all non-TTFields patients)
11. Evaluation of neurocognition for the subgroup of patients receiving TTFields in relation to those not receiving TTFields per treatment arm and combined for both treatment arms (all TTFields patients versus all non-TTFields patients)
12. Time to treatment failure, defined as premature stop of study treatment regardless of reason (progressive disease or toxicity)
13. OS in relation to baseline comorbidities
14. Treatment related neurotoxicity evaluated on MRI

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vaestra Goetalandsregionen

Sponsor organisation

Vaestra Goetalandsregionen

Address

Regionens Hus

City

Vänersborg

Postcode

462 80

Country

Sweden

Scientific contact point

Organisation

Vaestra Goetalandsregionen

Contact name

Asgeir Jakola

Public contact point

Organisation

Vaestra Goetalandsregionen

Contact name

Asgeir Jakola

Third parties 1

Region Oestergoetland

Sponsor organisation

Region Oestergoetland

Address

S S:t Lars, S:t Larsgatan 49 B, Linkopings S:t Lars S:t Larsgatan 49 B Linkopings S:t Lars

City

Linkoping

Postcode

582 24

Country

Sweden

Scientific contact point

Organisation

Vaestra Goetalandsregionen

Contact name

Annika Malmström

Public contact point

Organisation

Vaestra Goetalandsregionen

Contact name

Annika Malmström

Sponsor responsibilities

Article 77 compliance

Vaestra Goetalandsregionen

Contact point sponsor

Vaestra Goetalandsregionen

Article 77 implementation

Vaestra Goetalandsregionen

Locations

4 EU/EEA countries · 25 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 23 files

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

Application history

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