LAM561 With RT and TMZ for Adults With Glioblastoma (CLINGLIO)
Primary Glioblastoma, Glioblastoma Multiforme
About this trial
This is an interventional treatment trial for Primary Glioblastoma focused on measuring malignant
Eligibility Criteria
Inclusion criteria:
- Written informed consent, signed and dated
- Subjects who are able to understand and follow instructions during the trial
- Age ≥18 and ≤75
- Subjects with newly histologically confirmed intracranial malignant glioma (glioblastoma WHO Grade IV) that is IDH1 wildtype (local assessment) and who are scheduled to receive chemo-radiotherapy with temozolomide
- Ability to swallow and retain oral medication
- Centrally obtained MGMT promoter methylation status
- Subjects who underwent total or partial / incomplete resection and with the appropriate quantity of tumour tissue releasable for eligibility
- Karnofsky Performance Score (KPS) > 50 %
Female subjects with a childbearing potential must have a negative pregnancy test within one week before inclusion in the trial. Those female and male subjects admitted in the study must use a reliable method of contraception, for female subjects during the study period up until 32 days after last study treatment and for male 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 or toremifene, and age < 60 years, then FSH and oestradiol in the postmenopausal range), permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy), or otherwise incapable of pregnancy
- Or of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; male partner sterilization (the vasectomized partner should be the sole partner for that subject).
- A man who is sexually active and has not had a vasectomy must agree to use a barrier method of birth control e.g., either condom or partner with occlusive cap (diaphragm or cervical/vault caps).
- Adequate bone marrow function including: Absolute neutrophil count (ANC) ≥1,500/mm^3 or ≥1.5 x 10^9/L; Platelets ≥ 100,000/mm3 or ≥100 x10^9/L; Haemoglobin ≥ 9 g/dL (may have been transfused).
- Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal range (ULN), an aspartate aminotransferase (AST), level ≤ 2.5 × ULN, and an alanine aminotransferase (ALT) level ≤ 2.5 × ULN or, for subjects with documented metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN. Subjects with documented Gilbert disease are allowed if total bilirubin ≤ 3 x ULN
- Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
Exclusion Criteria:
- Known hypersensitivity to any component of the investigational product.
- Any other investigational drug within the preceding 30 days. Prior, concomitant, or planned concomitant treatment with anti-neoplastic aim including (but not limited) to NovoTumor Treatment Fields (Novo TTF), bevacizumab, intratumoural or intracavitary anti-neoplastic therapy (e.g Gliadel wafers), or other experimental therapeutics intended to treat the tumour.
- Subjects who underwent "only biopsy" resection
- Anticancer therapy within 4 weeks of study entry (6 weeks for mitomycin and nitrosoureas)
- Other major surgery within the preceding 30 days
- Allergy, hypersensitivity or other intolerability to temozolomide and its excipients, patients with hypersensitivity to dacarbazine and patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
- Unable to undergo MRI
- Presenting with diffuse midline gliomas or multifocal GBM (distant from the flare or contralateral) or rapid progression between early post-surgery MRI and pre-radiotherapy MRI
- Uncontrolled or significant cardiovascular disease
- A history of uncontrolled hyperlipidaemia and/or the need for concurrent lipid lowering therapy
- Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride, glipizide, glyburide or nateglanide)
- Past medical history of uncontrolled clinically significant active or chronic gastrointestinal disorders (for example, Crohn's disease, celiac disease, untreated stomach ulcers, etc) and gastro-inflammatory pathologies
- Uncontrolled diabetes mellitus, with glycated haemoglobin (HbA1c) levels at the screening visit of ≥7.5%
Cardiac disease, defined specifically as either
- Mean resting corrected QT interval (QTc) > 470 msec (for women) and > 450 ms (for men) obtained from 3 consecutive ECGs
- Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (example, complete left bundle branch block, third degree heart block)
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age
- Previous malignancies within the last three years other than ndGBM, except successfully treated squamous cell carcinoma of the skin, superficial bladder cancer, and in situ carcinoma of the cervix.
Sites / Locations
- Institut Cancerologie de L'Ouest (ICO)
- Centre Eugène Marquis (CEM)Recruiting
- Gustave Roussy University HospitalRecruiting
- Institut universitaire du cancerRecruiting
- Reaserch Fund of the Hadassah Medical Organization
- Istituto Nazionale Neurologico Carlo BestaRecruiting
- Istituto Nazionale Tumori "Regina Elena"Recruiting
- University of TurinRecruiting
- Hospital Universitario Reina SofíaRecruiting
- Hospital Universitario Virgen del RocíoRecruiting
- Hospital Universitari i Politécnic La Fe.Recruiting
- Hospital ClinicRecruiting
- Hospital del MarRecruiting
- Hospital Vall d'HebronRecruiting
- Hospital Clínico San CarlosRecruiting
- Hospital Universitario 12 De OctubreRecruiting
- Hospital Parc TauliRecruiting
- Freeman Hospital's Northern Centre of Cancer CareRecruiting
- University Hospitals Birmingham NHS Foundation Trust - New Queen Elizabeth HospitalRecruiting
- Cambridge university hospitalRecruiting
- The Royal Marsden HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Placebo Comparator
Experimental
Arm A: SoC + placebo for LAM561
Arm B: SoC + 12 g/day of LAM561
Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over ~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm A will receive placebo every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance (Adjuvant) Phase will be scheduled ~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm A will receive placebo every day during the first 3 weeks of each 28-day cycle and until progression. Patients will continue with Placebo after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment.
Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over ~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm B will receive LAM561 every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance Phase will be scheduled ~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm B will receive LAM561 during the Maintenance Phase. Patients will continue to be administered with LAM561 after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment.