LAM561 With RT and TMZ for Adults With Glioblastoma

Inclusion criteria:

1. Written informed consent, signed and dated

2. Subjects who are able to understand and follow instructions during the trial

3. Age ≥18 and ≤75

4. Subjects with newly histologically confirmed intracranial malignant glioma (glioblastoma WHO Grade IV) that is IDH1 wildtype (local assessment) and who arescheduled to receive chemo-radiotherapy with temozolomide

5. Ability to swallow and retain oral medication

6. Centrally obtained MGMT promoter methylation status

7. Subjects who underwent total or partial / incomplete resection and with theappropriate quantity of tumour tissue releasable for eligibility

8. Karnofsky Performance Score (KPS) > 50 %

9. Female subjects with a childbearing potential must have a negative pregnancy testwithin one week before inclusion in the trial. Those female and male subjectsadmitted in the study must use a reliable method of contraception, for femalesubjects during the study period up until 32 days after last study treatment and formale subjects up until 92 days after last study administration. Women must be:

• Either of NOT childbearing potential: postmenopausal (≥ 60 years of age, or < 60 years of age and amenorrhoea for 12 months in the absence of chemotherapy,tamoxifen, toremifene, or ovarian suppression with follicle-stimulating hormone (FSH) above 40 U/L and oestradiol below 30 ng/L, or if taking tamoxifen ortoremifene, and age < 60 years, then FSH and oestradiol in the postmenopausalrange), permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateralsalpingectomy), or otherwise incapable of pregnancy

• Or of childbearing potential and practicing a highly effective method of birthcontrol consistent with local regulations regarding the use of birth controlmethods for subjects participating in clinical studies: e.g., established useof oral, injected or implanted hormonal methods of contraception; placement ofan intrauterine device or intrauterine system; male partner sterilization (thevasectomized partner should be the sole partner for that subject).

10. A man who is sexually active and has not had a vasectomy must agree to use a barriermethod of birth control e.g., either condom or partner with occlusive cap (diaphragmor cervical/vault caps).

11. Adequate bone marrow function including: Absolute neutrophil count (ANC) ≥1,500/mm^3or ≥1.5 x 10^9/L; Platelets ≥ 100,000/mm3 or ≥100 x10^9/L; Haemoglobin ≥ 9 g/dL (mayhave been transfused).

12. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limitof normal range (ULN), an aspartate aminotransferase (AST), level ≤ 2.5 × ULN, andan alanine aminotransferase (ALT) level ≤ 2.5 × ULN or, for subjects with documentedmetastatic disease to the liver, AST and ALT levels ≤ 5 × ULN. Subjects withdocumented Gilbert disease are allowed if total bilirubin ≤ 3 x ULN

13. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/minaccording to the Cockcroft-Gault formula

Exclusion Criteria:

1. Known hypersensitivity to any component of the investigational product.

2. Any other investigational drug within the preceding 30 days. Prior, concomitant, orplanned concomitant treatment with anti-neoplastic aim including (but not limited)to NovoTumor Treatment Fields (Novo TTF), bevacizumab, intratumoural orintracavitary anti-neoplastic therapy (e.g Gliadel wafers), or other experimentaltherapeutics intended to treat the tumour.

3. Subjects who underwent "only biopsy" resection

4. Anticancer therapy within 4 weeks of study entry (6 weeks for mitomycin andnitrosoureas)

5. Other major surgery within the preceding 30 days

6. Allergy, hypersensitivity or other intolerability to temozolomide and itsexcipients, patients with hypersensitivity to dacarbazine and patients with rarehereditary problems of galactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption.

7. Unable to undergo MRI

8. Presenting with diffuse midline gliomas or multifocal GBM (distant from the flare orcontralateral) or rapid progression between early post-surgery MRI andpre-radiotherapy MRI

9. Uncontrolled or significant cardiovascular disease

10. A history of uncontrolled hyperlipidaemia and/or the need for concurrent lipidlowering therapy

11. Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride,glipizide, glyburide or nateglanide)

12. Past medical history of uncontrolled clinically significant active or chronicgastrointestinal disorders (for example, Crohn's disease, celiac disease, untreatedstomach ulcers, etc) and gastro-inflammatory pathologies

13. Uncontrolled diabetes mellitus, with glycated haemoglobin (HbA1c) levels at thescreening visit of ≥7.5%

14. Cardiac disease, defined specifically as either

15. Mean resting corrected QT interval (QTc) > 470 msec (for women) and > 450 ms (for men) obtained from 3 consecutive ECGs

16. Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG (example, complete left bundle branch block, third degree heartblock)

17. Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalaemia, potential for Torsades de Pointes,congenital long QT syndrome, family history of long QT syndrome or unexplainedsudden death under 40 years of age

18. Previous malignancies within the last three years other than ndGBM, exceptsuccessfully treated squamous cell carcinoma of the skin, superficial bladdercancer, and in situ carcinoma of the cervix.